Benzimidazole derivatives, their production and use

ABSTRACT

Benzimidazole derivatives of the formula (I):                    
     wherein the ring A is a benzene ring which may optionally contain substitution in addition to the R′ group; R 1  is hydrogen or an optionally substituted hydrocarbon residue; R 2  is a group capable of forming an anion or a group convertible thereinto; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; R′ is carboxyl, an ester thereof, an amide thereof or a group capable of forming an anion or convertible to an anion; Y is —O—, —S(O) m — or —N(R 4 )— wherein m is an integer of  0, 1  or  2  and R 4  is hydrogen or an optionally substituted alkyl group; and n is an integer of  1  or  2;  and the pharmaceutically acceptable salts thereof, have potent angiotensin II antagonistic activity and antihypertensive activity, thus being useful as therapeutic agents for treating circulatory system diseases such as hypertensive diseases, heart diseases, strokes, cerebral apoplexy and nephritis.

This application is a divisional of application Ser. No. 09/280,094,filed Mar. 29, 1999, now U.S. Pat. No. 6,004,989, which is in turn adivisional of application Ser. No. 08/924,919, filed Sep. 8, 1997, nowU.S. Pat. No. 5,462,481 which is in turn a divisional of applicationSer. No. 08/715,100, filed Sep. 17, 1996 now U.S. Pat. No. 5,703,110,which is in turn a divisional of application Ser. No. 08/131,667, filedOct. 5, 1993, now U.S. Pat. No. 5,705,517, which is in turn a divisionalof application Ser. No. 08/058,739, filed May 10, 1993, now U.S. Pat.No. 5,401,764, which is in turn is a divisional of Ser. No. 07/997,703,filed Jan. 5. 1993, now U.S. Pat. No. 5,328,919, which is in turn adivisional of Ser. No. 07/687,238, filed Apr. 18, 1991, now U.S. Pat.No. 5,196,144.

FIELD OF THE INVENTION

The present invention relates to novel benzimidazole derivatives havingpotent pharmacological actions and intermediates for the preparationthereof. More particularly, the present invention relates to compoundshaving potent anti-hypertensive activity and strong angiotensin IIantagonistic activity, which are useful as therapeutic agents fortreating circulatory diseases such as hypertensive diseases, heartdiseases (e.g. hypercardia, heart failure, cardiac infarction, etc.),strokes, cerebral apoplexy, nephritis, etc.

BACKGROUND OF THE INVENTION

The renin-angiotensin system is involved in the homeostatic function tocontrol systemic blood pressure, the volume of body fluid, balance amongthe electrolytes, etc., associated with the aldosterone system.Development of angiotensin II converting enzyme inhibitors (ACEinhibitor) (this converting enzyme produces angiotensin II whichpossesses a strong vasoconstrictive action) has clarified the relationbetween the renin-angiotensin system and hypertension. Since angiotensinII constricts blood vessel to elevate blood pressure via the angiotensinII receptors on the cellular membranes, angiotensin II antagonists, likethe ACE inhibitor, wouLd be useful in treating hypertension caused byangiotensin.

It has been reported that various angiotensin II analogues such assaralasin, [Sar¹,Ile⁸]A II, and the like, possess potent angiotensin IIantagonist activity.

It has, however, been reported that, when peptide antagonists areadministered parenterally, their actions are not prolonged and, whenadministered orally, they are ineffective (M. A. Ondetti and D. W.Cushman, Annual Reports in Medicinal Chemistry, 13, 82-91 (1978)).

It would be highly desirable to develop a non-peptide angiotensin IIantagonist which overcomes these drawbacks. In the eariest studies inthis field, imidazole derivatives having angiotensin II antagonistactivity have been disclosed in Japanese Patent Laid Open No.71073/1981; No. 71074/1981; No. 92270/1982; No. 157768/1983; U.S. Pat.Nos. 4,355,040, 4,355,040, etc. Later, improved imidazole derivativesare disclosed in European Patent Laid Open No. 0253310, No. 0291969, No.0324377, Japanese Patent Laid Open No. 23868/1988; and No. 117876/1989.Further, pyrole, pyrazole, and triazole derivatives are disclosed asangiotensin II antagonists in European Patent Laid Open No. 0323841, andJapanese Patent Laid Open No. 287071/1989.

U.S. Pat. No. 4,880,804 discloses benzimidazole derivatives having anangiotensin II receptor antagonistic action, which are intravenouslyactive in vivo in rats with renal hypertension. Examples of suchbenzimidazole derivatives are those represented by the following formula(A):

wherein substituents, for example, in the 5- and/or 6-position arehydroxymethyl, methoxy, formyl, chloro, or carboxy. Although mostcompounds among those exemplified are orally inactive, it is said thatonly the 6-hydroxymethyl and 6-chloro compounds are orally effective(100 mg/kg or less). It is, however, believed that the activity of eventhese disclosed compounds is insufficient for clinical uses.

SUMMARY OF THE INVENTION

The present invention provides novel benzimidazole derivatives havingpotent anti-hypertensive activity and strong angiotensin II antagonisticaction, which are of practical value in clinical use as therapeuticagents.

The present inventors considered that compounds functioning to controlthe renin-angiotensin system as well as clinically useful for thetreatment of circulatory diseases such as hypertensive diseases, heartdiseases (e.g. hypercardia, heart failure, cardiac infarction, etc.),strokes, cerebral apoplexy, etc. are required to have potent angiotensinII receptor antagonistic activity and to exert strong oral andlong-lasting angiotensin II antagonist action. Extensive investigationswere made based on those consideration. As a result of this research,the present inventors have succeeded in synthesizing novel 2-substitutedbenzimidazole derivatives (I) possessing highly angiotensin II receptorantagonistic activity as well as exerting strong oral and long-lastingangiotensin II antagonistic and anti-hypertensive action and developedthe present invention.

The present invention relates to benzimidazole derivatives having theformula I:

wherein the ring A is a benzene ring which may optionally containsubstitution in addition to the R′ group; R¹ is hydrogen or anoptionally substituted hydrocarbon residue; R² is a group capable offorming an anion or a group convertible thereinto; X is a direct bond ora spacer having an atomic length of two or less between the phenylenegroup and the phenyl group; R′ is carboxyl, an ester thereof, an amidethereof or a group capable of forming an anion or convertible to ananion; Y is —O—, —S(O)_(m)— or —N(R⁴)— wherein m is an integer of 0, 1or 2 and R⁴ is hydrogen or an optionally substituted alkyl group; and nis an integer of 1 or 2; and the pharmaceutically acceptable saltsthereof.

These compounds are unexpectedly potent angiotensin II antagonists whichare of value in the treatment of circulatory system diseases such ashypertensive diseases, heart diseases, strokes, nephritis, etc.

Another aspect of the present invention relates to pharmaceuticalcompositions comprising an effective amount of the benzimidazolederivative having the formula I and a pharmaceutically acceptablecarrier useful in treating circulatory system diseases such ashypertensive diseases, heart diseases, strokes, renal failure,nephritis, etc., and processes for preparing such compounds andcompositions.

Still another aspect of the present invention relates to a method fortreating said circulatory system diseases of animals, which comprisesadministering an effective amount of the benzimidazole derivativeshaving the formula I or the pharmaceutical composition thereof to saidanimal.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a X ray scattering chart obtained in Experimental Example1.

FIG. 2 depicts an IR spectrum pattern obtained in Experimental Example1.

FIG. 3 depicts a differential scanning calorimeter pattern obtained inExperimental Example 1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides the benzimidazole derivatives (I) and thepharmaceutically acceptable salts thereof, which possess strongangiotensin II antagonist activity and are of value in the treatment ofcirculatory diseases such as hypertensive diseases, heart diseases,strokes, cerebral diseases, nephritis, etc., pharmaceutical compositionscomprising an effective amount of the benzimidazole derivative havingthe formula I and a pharmaceutically acceptable carrier useful intreating said circulatory diseases, and processes for preparing suchcompounds and compositions.

The present invention further provides a method for treating saidcirculatory system diseases of animals, which comprises administering aneffective amount of the benzimidazole derivative (I) or thepharmaceutical composition thereof to said animal.

An important group of compounds according to the present invention arethe compounds of the formula I″:

wherein the ring A is a benzene ring which may optionally containsubstitution in addition to the R′ group; R¹ is hydrogen or anoptionally substituted hydrocarbon residue; R² is a group capable offorming an anion or a group convertible thereinto; X is a direct bond ora spacer having an atomic length of two or less between the phenylenegroup and the phenyl group; R′ is carboxyl, an ester thereof or an amidethereof ; Y is —O—, —S(O)_(m)— or —N(R⁴)— wherein m is an integer of 0,1 or 2 and R⁴ is hydrogen or an optionally substituted alkyl group; andn is an integer of 1 or 2; and the pharmaceutically acceptable saltsthereof.

With regard to the foregoing formula (I), hydrocarbon residues for R¹include, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, andaralkyl groups. Among them, alkyl, alkenyl, and cycloalkyl groups arepreferable.

Alkyl groups for R¹ are lower alkyl groups having 1 to about 8 carbonatoms, which may be straight or branched, and include, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,pentyl, i-pentyl, hexyl, heptyl, octyl, and the like.

Alkenyl groups for R¹ are lower alkenyl groups having 2 to about 8carbon atoms, which may be straight or branched, and include, forexample, vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, octenyl, andthe like.

Alkynyl groups for R¹ are lower alkynyl groups having 2 to about 8carbon atoms, which may be straight or branched, and include, forexample, ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-octynyl, and thelike.

Cycloalkyl groups for R¹ are lower cycloalkyl groups having 3 to about 6carbon atoms, and include, for example, cyclopropyl, cyclobutyl,cyclopentyl, and the like.

The above-mentioned alkyl, alkenyl, alkynyl, and cycloalkyl groups maybe substituted with hydroxyl, an optionally substituted amino group(e.g. amino, methylamino, etc.), halogen, a lower (C₁₋₄) alkoxy group orthe like.

Aralkyl groups for R¹ include, for example, phenyl-lower (C₁₋₄) alkylsuch as benzyl, phenethyl, and the like, and the aralkyl group may besubstituted with, for example, halogen (e.g. F, Cl, Br, etc.), nitro,lower (C₁₋₄) alkoxy (e.g. methoxy, ethoxy, etc.), lower (C₁₋₄) alkyl(e.g. methyl, ethyl, etc.), or the like at various positions of thebenzene ring.

Aryl groups for R¹ include, for example, phenyl and the aryl group maybe substituted with, for example, halogen (e.g. F, Cl, Br, etc.), nitro,lower (C₁₋₄) alkoxy (e.g. methoxy, ethoxy, etc.), lower (C₁₋₄) alkyl(e.g. methyl, ethyl, etc.), or the like at various positions of thebenzene ring.

Among the above-mentioned groups for R¹, preferred examples areoptionally substituted alkyl and alkenyl groups (e.g. lower (C₁₋₅) alkyland lower (C₂₋₅) alkenyl groups optionally substituted with hydroxyl, anamino group, halogen or a lower (C₁₋₄) alkoxy group).

Examples of groups capable of forming an anion and groups convertiblethereinto for R² include carboxyl, tetrazolyl, trifluoromethanesulfonicamide (—NHSO₂CF₃), phosphoric acid, sulfonic acid, cyano, lower (C₁₋₄)alkoxycarbonyl, and the like. These groups may be protected with, forexample, an optionally substituted lower alkyl group (e.g. lower (C₁₋₄)alkoxymethyl, optionally substituted arylmethyl, etc.) or an acyl group(e.g. lower (C₂₋₅) alkanoyl, optionally substituted benzoyl, etc.). Suchgroups may include those which are capable of forming anions orconvertible thereinto either chemically or under biological and/orphysiological conditions (for example, in vivo reaction such asoxidation-reduction or hydrolysis catalyzed by in vivo enzymes).

The compounds wherein R² is a group capable of forming an anion orconvertible thereinto chemically (e.g. by oxidation, reduction orhydrolysis) (for example, an optionally protected tetrazolyl group (e.g.a group having the formula:

wherein R is methyl, triphenylmethyl, 2-tetrahydropyranyl, tert-butyl,methoxymethyl, ethoxymethyl, or optionally substituted benzyl such asp-methoxybenzyl and p-nitrobenzyl), cyano and the like), are useful assynthetic intermediates.

Among the above-mentioned groups for R², preferred examples aretetrazolyl groups optionally protected with optionally substituted loweralkyl or acyl, carboxyl groups optionally protected with optionallysubstituted lower alkyl, and trifluoromethanesulfonic amide.

Examples of carboxyl, esters thereof or amides thereof for R′ include,for example, groups having the formula: —CO—D′ wherein D′ is hydroxyl,optionally substituted amino (e.g. amino, N-lower (C₁₋₄) alkylamino,N,N-dilower (C₁₋₄) alkyl amino, etc.), or optionally substituted alkoxy[e.g. lower (C₁₋₄) alkoxy optionally substituted with hydroxyl,optionally substituted amino (e.g. amino, dimethylamino, diethylamino,piperidino, morpholino, etc.), halogen, lower (C₁₋₆) alkoxy, lower(C₁₋₆) alkylthio or optionally substituted dioxolenyl (e.g.5-methyl-2-oxo-1,3-dioxolen-4-yl, etc.) on the alkyl moiety and groupshaving the formula: —OCH(R⁷)OCOR⁸ wherein R⁷ is hydrogen, straight orbranched lower alkyl having 1 to 6 carbon atoms (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl,neopentyl, etc.), or cycloalkyl having 5 to 7 carbon atoms (e.g.cyclopentyl, cyclohexyl, cycloheptyl, etc.) and R⁸ is straight orbranched lower alkyl having 1 to 6 carbon atoms (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, etc.), straight or branched lower alkenyl having 2to about 8 carbon atoms (e.g. vinyl, propenyl, 2-butenyl, 3-butenyl,isobutenyl, octenyl, etc.), cycloalkyl having 5 to 7 carbon atoms (e.g.cyclopentyl, cyclohexyl, cycloheptyl, etc.), lower (C₁₋₃) alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, etc.) which is substituted withoptionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms(e.g. benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl,cyclohexylmethyl, etc.), lower (C₂₋₃) alkenyl (e.g. vinyl, propenyl,allyl, isopropenyl, etc.) which is substituted with optionallysubstituted aryl or cycloalkyl having 5 to 7 carbon atoms (e.g.cinnamyl, etc.), optionally substituted aryl (e.g. phenyl, p-tolyl,naphthyl, etc.), straight or branched lower alkoxy having 1 to 6 carbonatoms (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, lsobutoxy,sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.),straight or branched lower alkenyloxy having 2 to about 3 carbon atoms(e.g. allyloxy, isobutenyloxy, etc.), cycloalkyloxy having 5 to 7 carbonatoms (e.g. cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), lower(C₁₋₃) alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, etc.) whichis substituted with optionally substituted aryl or cycloalkyl having 5to 7 carbon atoms (e.g. benzyloxy, phenethyloxy, cyclopentylmethyloxy,cyclohexylmethyloxy, etc.), lower (C₂₋₃) alkenyloxy (e.g. vinyloxy,propenyloxy, allyloxy, isopropenyloxy, etc.) which is substituted withoptionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms(e.g. cinnamyloxy, etc.), optionally substituted aryloxy (e.g. phenoxy,p-nitrophenoxy, naphthoxy, etc.)]. Examples of groups capable offorming.an anion and groups convertible thereinto for R′ may include,for example, tetrazolyl groups optionally protected with optionallysubstituted lower alkyl such as lower (C₁₋₄) alkyl and lower (C₁₋₄)alkoxy lower (C₁₋₄) alkyl or acyl such as lower (C₂₋₅) alkanoyl andoptionally substituted benzoyl, trifluoromethanesulfonic amide,phosphoric acid, sulfonic acid, and the like. Examples of substituentsfor R′ include —COOH and salts thereof, —COOMe, —COOEt, —COOtBu, —COOPr,pivaloyloxymethoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl,5-methyl-2-oxo-1,3-dioxolen-4-ylmethyloxycarbonyl,acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl,n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl,1-(ethoxycarbonyloxy)ethoxy-carbonyl, 1-(acetyloxy)ethoxycarbonyl,1-(isobutyryloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl,benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl,cyclopentylcarbonyloxymethoxycarbonyl, etc. Such groups may includethose which are capable of forming anions (e.g. —COO—, derivativesthereof, etc.) or convertible thereinto either chemically or underbiological and/or physiological conditions (for example, in vivoreaction such as oxidation-reduction or hydrolysis catalyzed by in vivoenzymes).

The benzene ring A may optionally contain substitution in addition tothe R′ group and such substituents include halogen [e.g. F, Cl, Br,etc.); nitro; cyano; optionally substituted amino (e.g. amino, N-lower(C₁₋₄) alkyl such as methylamino and ethylamino, N,N-dilower (C₁₋₄)alkyl amino such as dimethylamino and diethylamino, N-arylamino such asphenylamino and naphthylamino, N-aralkylamino such as benzylamino andnaphthylmethylamino, and alicyclic amino such as morpholino, piperidino,piperazino and N-phenylpiperazino]; groups having the formula: —W—R¹³wherein W is a chemical bond, —O—, —S—, or

and R¹³ is hydrogen or an optionally substituted lower alkyl group (e.g.lower (C₁₋₄) alkyl optionally substituted with hydroxyl, optionallysubstituted amino (e.g. amino, dimethylamino, diethylamino, piperidino,morpholino, etc.), halogen or lower (C₁₋₄) alkoxy, etc.); groups havingthe formula: —(CH₂)_(s)—CO—D wherein D is hydrogen, hydroxyl, optionallysubstituted amino (e.g. amino, N-lower (C₁₋₄) alkylamino, N,N-dilower(C₁₋₄) alkyl amino, etc.), or optionally substituted alkoxy [e.g. lower(C₁₋₆) alkoxy optionally substituted with hydroxyl, optionallysubstituted amino (e.g. amino, dimethylamino, diethylamino, piperidino,morpholino, etc.), halogen, lower (C₁₋₆) alkoxy, lower (C₁₋₆) alkylthioor optionally substituted dioxolenyl (e.g.5-methyl-2-oxo-1,3-dioxolen-4-yl, etc.) on the alkyl moiety and groupshaving the formula: —OCH(R⁹)OCOR¹⁰ wherein R⁹ is hydrogen, straight orbranched lower alkyl having 1 to 6 carbon atoms (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl,neopentyl, etc.), or cycloalkyl having 5 to 7 carbon atoms (e.g.cyclopentyl, cyclohexyl, cycloheptyl, etc.) and R¹⁰ is straight orbranched lower alkyl having 1 to 6 carbon atoms (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, etc.), straight or branched lower alkenyl having 2to about 8 carbon atoms (e.g. vinyl, propenyl, 2-butenyl, 3-butenyl,isobutenyl, octenyl, etc.), cycloalkyl having 5 to 7 carbon atoms (e.g.cyclopentyl, cyclohexyl, cycloheptyl, etc.), lower (C₁₋₃) alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, etc.) which is substituted withoptionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms(e.g. benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl,cyclohexylmethyl, etc.), lower (C₂₋₃) alkenyl (e.g. vinyl, propenyl,allyl, isopropenyl, etc.) which is substituted with optionallysubstituted aryl or cycloalkyl having 5 to 7 carbon atoms (e.g.cinnamyl, etc.), optionally substituted aryl (e.g. phenyl, p-toluyl,naphthyl, etc.), straight or branched lower alkoxy having 1 to 6 carbonatoms (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.),straight or branched lower alkenyloxy having 2 to about 8 carbon atoms(e.g. allyloxy, isobutenyloxy, etc.), cycloalkyloxy having 5 to 7 carbonatoms (e.g. cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), lower(C₁₋₃) alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, etc.) whichis substituted with optionally substituted aryl or cycloalkyl having 5to 7 carbon atoms (e.g. benzyloxy, phenethyloxy, cyclopentylmethyloxy,cyclohexylmethyloxy, etc.), lower (C₂₋₃) alkenyloxy (e.g. vinyloxy,propenyloxy, allyloxy, isopropenyloxy, etc.) which is substituted withoptionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms(e.g. cinnamyloxy, etc.), optionally substituted aryloxy (e.g. phenoxy,p-nitrophenoxy, naphthoxy, etc.)], and p is 0 or 1; tetrazolyloptionally protected with, for example, an optionally substituted loweralkyl group (e.g. lower (C₁₋₄) alkoxymethyl, optionally substitutedarylmethyl, etc.) or an acyl group (e.g. lower (C₂₋₅) alkanoyl,optionally substituted benzoyl, etc.); trifluoromethanesulfonic amide;phosphoric acid; sulfonic acid; etc.

One or two of these substituents may be substituted at various positionsof the benzene ring. When two substituents are present at the 4 and 5 or5 and 6 positions on the ring A, they may be taken together to form aring (e.g. benzene, etc.). Such rings may be substituted with the samegroups as for the ring A.

X shows that the adjacent phenylene group is bonded to the phenyl groupdirectly or through a spacer with an atomic chain of 2 or less. As thespacer, any one can be exemplified, so long as it is a divalent chain inwhich the number of atoms constituting the straight chain is 1 or 2, andit may have a side chain. Examples of such spacers include lower (C₁₋₄)alkylene,

The most preferred X is a chemical bond between the phenylene group andthe phenyl group.

Y represents that R¹ is bonded to the 2-position of benzimidazolethrough a hetero atom. Examples of Y include —O—, —SO_(m)— wherein m is0, 1, or 2, —N(R⁴)— wherein R⁴ is hydrogen or an optionally substitutedlower (C₁₋₄) alkyl group, and the like, preferably —O—, —S—, and —NH—,more preferably —O— and —S—, especially —O—. R¹ and R⁴ may be takentogether with the N atom attached thereto to form a heterocyclic ring(e.g. piperidino, morpholino, etc.).

When R¹=H, the compounds having the formula (I) [Compound (I)] can existin two tautomeric forms.

When the compounds of the present invention have several asymetriccarbon atoms, they can thus exist in several stereochemical forms. Theinvention includes the mixture of isomers and the individualstereoisomers. It is intended that the present invention includesgeometrical isomers, rotational isomers, enantiomers, racemates, anddiastereomers.

The compounds of the present invention can exist in any pro-drug form ofthose wherein R′ is carboxyl or the anion therefrom.

Among the compounds represented by the above formula (I), a preferredembodiment of the invention is a compound of the formula:

wherein R¹ is lower (C₁₋₅) alkyl optionally substituted with hydroxyl,amino, halogen, or a lower (C₁₋₄) alkoxy group (inter alia lower (C₂₋₃)alkyl); R′ is —CO—D′ wherein D′ is hydroxyl, amino, N-lower (C₁₋₄)alkylamino, N,N-dilower (C₁₋₄) alkyl amino, or lower (C₁₋₄) alkoxyoptionally substituted with hydroxyl, amino, halogen, lower (C₁₋₄)alkoxy, lower (C₂₋₆) alkanoyloxy (e.g. acetyloxy, pivaloyloxy, etc.) or1-lower (C₁₋₆) alkoxycarbonyloxy (e.g. methoxycarbonyloxy,ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.) on the alkyl moiety,or tetrazolyl optionally protected with an optionally substituted lower(C₁₋₄) alkyl or acyl group (e.g. lower (C₂₋₅) alkanoyl, benzoyl, etc.);R² is tetrazolyl optionally protected with an optionally substitutedlower (C₁₋₄) alkyl (e.g. methyl, triphenylmethyl (trityl),methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) oracyl group (e.g. lower (C₂₋₅) alkanoyl, benzoyl, etc.), or carboxyloptionally protected with an optionally substituted lower (C₁₋₄) alkylgroup (e.g. methyl, triphenylmethyl (trityl), methoxymethyl,ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.); R″ is hydrogen,halogen, lower (C₁₋₄) alkyl, lower (C₁₋₄) alkoxy, nitro or —CO—D″wherein D″ is hydroxyl or lower (C₁₋₂) alkoxy optionally substitutedwith hydroxyl, lower (C₁₋₄) alkoxy, lower (C₂₋₆) alkanoyloxy (e.g.acetyloxy, pivaloyloxy, etc.) or 1-lower (C₁₋₆) alkoxycarbonyloxy (e.g.methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.)on the alkyl moiety, or amino optionally substituted with lower (C₁₋₄)alkyl (inter alia hydrogen, lower (C₁₋₄) alkyl, or halogen, morepreferably hydrogen); and Y is —O—, —S—, or —N(R⁴)— wherein R⁴ ishydrogen or an lower (C₁₋₄) alkyl group; and the pharmaceuticallyacceptable salts thereof.

The compounds (I) of the present invention may be prepared by severalreaction schemes, as illustrated below for a preferred compound.

wherein R¹, R², R′, A, X, Y and n have the above-defined meanings and Zis halogen.

wherein each group has the above-defined meaning.

wherein R¹, R′, A, X, Y and n have the above-defined meanings, and R⁵ isoptionally substituted lower (C₁₋₅) alkyl.

wherein each group has the above-defined meaning.

wherein each group has the above-defined meaning.

wherein each group has the above-defined meaning.

wherein each group has the above-defined meaning.

wherein each group has the above-defined meaning.

wherein each group has the above-defined meaning.

wherein each group has the above-defined meaning.

wherein each group has the above-defined meaning.

wherein each group has the above-defined meaning.

wherein each group has the above-defined meaning.

wherein A, R, R¹, X, Y and n have the above-defined meanings, and R⁶ islower (C₁₋₆) alkyl optionally substituted with lower (C₂₋₆) alkanoyloxy,1-lower (C₁₋₆) alkoxycarbonyloxy or the like as defined for R′.

The reaction as illustrated in Scheme A is an alkylation using analkylating agent in the presence of a base. One molar portion of thecompound (II) is employed with approximately 1 to 3 moles of the baseand 1-3 moles of the alkylating agent. The reaction is conventionallyconducted in solvents such as dimethylformamide, dimethylacetamide,dimethylsulfoxide, acetonitrile, tetrahydrofuran, acetone,ethylmethylketone, and the like. Examples of such bases include sodiumhydride, potassium t-butoxide, potassium carbonate, sodium carbonate,and the like. Examples of such alkylating agents include substitutedhalides (e.g. chlorides, bromides, iodides, and the like), substitutedsulfonate esters (e.g. p-toluenesulfonate esters, and the like), etc.The reaction conditions may vary depending on the combination of thebase and the alkylating agent. Advantageously, the reaction is carriedout at ice-cooling to room temperature for about 1-10 hours.

In the said alkylation, a mixture of two isomers, (I) and (I′″) isusually obtained depending on the position of the N atom to bealkylated. While the production ratio of Compound (I) and Compound (′″)varies with the reaction conditions employed and the substituents on thebenzimidazole ring, these two compounds can be obtained easily as pureproducts respectively by conventional isolation and/or purificationmethods (e.g. recrystallization, column chromatography and the like).

The nitrile compound (Ia) is reacted with various azides to form thetetrazole compound (Ib) as illustrated in Scheme B. One molar portion ofthe compound (Ia) is employed with 1-5 moles of the azide. The reactionis conventionally conducted in solvents such as dimethylformamide,dimethylacetamide, toluene, benzene, and the like. Examples of suchazides include trialkyltin azide (e.g. trimethyltin azide, tributyltinazide, triphenyltin azide, etc.), hydrogen azide and ammonium saltsthereof, and the like. In the case where the organotin azide compound isemployed, 1-4 moles of the azide are employed per compound (Ia) and thereaction is carried out in toluene or benzene by heating under refluxfor a period of 1-4 days. When the hydrogen azide or its ammonium saltis used, 1-5 moles of sodium azide and ammonium chloride or tertiaryamine (e.g. triethylamine, tributylamine, etc.) are employed percompound (Ia) and the reaction is conducted in dimethylformamide atabout 100° C.-120° C. for about 1-4 days. During this reaction, it ispreferable to facilitate the reaction by adding an appropriate amount ofsodium azide and ammonium chloride. In this case, improvement maysometimes be observed in reaction time and yield by the addition of theazide compound in suitable fractions.

The ester (Ic) is hydrolyzed in the presence of alkali to give thecarboxylic acid (Id) as illustrated in Scheme C. This reaction isconducted usually in a solvent such as aqueous alcohol (e.g. methanol,ethanol, methyl cellosolve, etc.) by using alkali in an amount of about1 to 3 mol. relative to 1 mol. of Compound (Ic). Examples of suchalkalis include sodium hydroxide, potassium hydroxide, etc. The reactionis conducted at temperatures ranging from room temperature to about 100°C. for about 1 to 10 hours, preferably around the boiling point of thesolvent for about 2 to 5 hours.

The 2-alkoxy derivative (Ie) is obtained by reacting phenylenediamine(IV) with alkyl orthocarbonate as illustrated in Scheme D. The reactionis conducted in the presence of an acid by using alkyl orthocarbonate ofabout 1 to 3 mol. relative to Compound (IV). Examples of such alkylorthocarbonates include orthocarbonats of, for example, methyl, ethyl,propyl, isopropyl, butyl, etc. And, by using ,for example, acetic acidor p-toluenesulfonic acid, the reaction is accelerated to afford aring-closed compound in a good yield. As the reaction solvent,halogenated hydrocarbons and ethers can be employed but, usually, it ismore convenient to conduct the reaction without a solvent. The reactionis usually conducted at about 70 to 100° C. for about 1 to 5 hours. Inthis reaction, a dialkoxyimino compound is produced as the reactionintermediate, which is then ring-closed into the 2-alkoxy compound (Ie)in the presence of the acid in the reaction system. It is also possibleto isolate the reaction intermediate, which is then subjected toring-closure reaction in the presence of an acid to form the 2-alkoxycompound (Ie).

The phenylenediamino compound (IV) is reacted with various reagents togive the 2-keto compound (or the 2-hydroxy compound, If) as illustratedin Scheme E. This reaction is conducted by using a carbonylating reagent(e.g. urea, diethyl carbonate, bis(1-imidazolyl)ketone, etc.) in anamount of about 1 to 5 mol. relative to 1 mol. of Compound (IV) and,usually, by using, among others, halogenated hydrocarbons (e.g.methylene chloride, chloroform, etc.), alcohols (e.g. methanol, ethanol,etc.) or amides (e.g. dimethylformamide, dimethylacetamide, etc.).

The 2-hydroxy compound (If) is selectively O-alkylated wilth a Meerweinreagent to give the 2-alkoxy compound (Ig) as illustrated in Scheme F.This reaction is conducted by using the Meerwein reagent in an amount ofabout 1 to 3 mol. relative to Compound (If), usually, employing, as thesolvent, halogenated hydrocarbons (e.g. methylene chloride, chloroform,etc.) or ethers (e.g. methyl ether, ethyl ether, etc.). Examples of suchMeerwein reagents include, among others, t-rimethyl oxonium fluoroborate(Me₃O⁺BF₄ ⁻), triethyl oxonium fluoroborate (Et₃O⁺BF₄ ⁻), etc. These arepreferably used by in situ preparation according to the method describedin literature references [H. Meerwein, Org. Syn. 46. 113 and 120(1966)].The reaction is preferably conducted at temperatures ranging from aboutroom temperatures to the boiling point of the solvent used for about 2to 20 hours.

The phenylene diamino compound (IV) is reacted with various reagents inan organic solvert to give the 2-mercapto compound (Ih) as illustratedin Scheme G. Relative to 1 mol. of the phenylene diamino compound (IV),about 1 to 3 mol. of a thiocarbonylating agent (e.g. carbon disulfide,thiourea, potassium xanthate, etc.) or isothiocyanate (e.g. methylisothiocyanate, ethyl isothiocyanate, etc.) is used. As the reactionsolvent, alcohols (e.g. methanol, ethanol, etc.), amides (e.g.dimetylformamide, dimethylacetamide, etc.) or the like can be used. Thereaction is preferably conducted at temperatures ranging from roomtemperatures to the boiling point of the solvent used for about 5 to 20hours.

The 2-mercapto compound (Ih) is alkylated in the presence of a base inan organic solvent to give the alkylthio compound (Ii) as illustrated inScheme H. The reaction is conducted by using, relative to 1 mol. ofCompound (Ih), about 1 to 3 mol. of the base and about 1 to 3 mol. ofthe alkylating agent usually in a solvent such as dimethylformamide,dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethylmethyl ketone, ethanol, methanol and water. As the base, there is usedsodium hydroxide, potassium carbonate, sodium carbonate, sodium hydride,potassium t-butoxide, potassium hydroxide or the like. As the alkylatingagent, there is used, for example, a halide (e.g. methyl iodide, ethyliodide, propyl iodide, butyl iodide, and bromide or chloride thereof).The reaction is conducted usually at temperatures ranging fromice-cooling to the boiling point of the solvent used, while the reactionconditions vary with the base, the alkylating agent and the solventemployed.

The phenylenediamine (IV) is reacted with isothiocyanate to form thethiourea compound (V), which is then subjected todesulfurization-cyclization to give the 2-substituted amino compound(Ij) as illustrated in Scheme I. The reaction is conducted by usingabout 1 to 3 mol. of isothiocyanate relative to 1 mol. of Compound (IV)usually in halogenated hydrocarbons (e.g. chloroform, methylenechloride, etc.), ethers (e.g. tetrahydrofuran, dioxane, etc.), aromatichydrocarbons (e.g. benzene, toluene, etc.), alcohols (e.g. methanol,ethanol, etc.), acetonitrile, dimethylformamide or the like. Thereaction can also be conducted without these solvents. Examples of suchisothiocyanates include isothiocyanates of methyl, ethyl, propyl,isopropyl, butyl, etc. The reaction is conducted preferably attemperatures ranging from room temperatures to about 50° C. for about 10to 60 hours. The desulfurization-cyclization can be conducted in amanner as described below.

The reaction is conducted, in halogenated hdyrocarbons (e.g. HgCl₂), byusing about 1 to 3 mol. of a metal halide (e.g. HgCl₂) relative to 1mol. of the thiourea (V) obtained by the above-mentioned method. Thereaction is conducted preferably at temperatures ranging from roomtemperature to the boiling point of a solvent employed for about 3 to 10hours. The reaction can also be conducted by using about 1 to 3 mol. ofmethyl iodide relative to 1 mol. of thiourea (V) in alcohols (e.g.methanol or ethanol), preferably at temperatures ranging from roomtemperature to about the boiling point of the solvent for about 3 to 15hours.

The 2-halogeno compound (V′) readily prepared from the compound (If) isreacted with various nucleophilic reagents to form the compound (I) asillustrated in Scheme I′. The reaction can be carried out according tothe procedures as described in known references (e.g. D. Harrison and J.J. Ralph, J. Chem. Soc., 1965, 236). The compound (If) is reacted with ahalogenating reagent (e.g. phosphorus oxychloride, phosphorustrichloride, etc.) to form the 2-halogeno compound (V′) which is reactedwith various nucleophilic reagents (e.g. alcohols, mercaptans, amines,etc.) in a suitable organic solvent to give the compound (I). Thereaction conditions may vary depending on the nucleophilic reagentemployed. Upon the reaction with alcohols, alcoholates (e.g. sodiummethoxide, sodium ethoxide, sodium propoxide, etc.) derived fromalcohols and sodium metal are preferably used. As the reaction solvent,alcohols then used for nucleophilic reagents can be employed. Relativeto 1 mol. of the compound (V′), there is used about 2 to 5 mol. of analcoholate. Advantageously, the reaction is usually conducted atapproximately the boiling point of the solvent used for about 1 to 3hours. Upon the reaction with amines, about 3 to 10 mol. of an amine isused relative to 1 mol. of the compound (V′). As the reaction solvent,alcohols (e.g. ethanol, etc.) are employed but, an excess amount ofamines can be used. Advantageously, the reaction is usually conducted attemperatures ranging from about the boiling point of the solvent to 150°C. for about 1 to 10 hours. Upon the reaction with mercaptans, about 2to 5 mol. of a mercaptan is used relative to 1 mol. of the compound(V′). The reaction is preferably conducted in the presence of about 1 to3 mol. of an base (e.g. sodium carbonate, potassium carbonate, etc.)relative to Compound (IV). Examples of solvents include acetonitrile,alcohols, halogenated hydrocarbons (e.g. chloroform, dichloroethane,etc.), ethers (e.g. tetrahydrofuran, dioxane, etc.) or amides (e.g.dimethylformamide, dimethylacetamide, etc.). The reaction can beconducted preferably at temperatures ranging from 50° C. to about theboiling point of the solvent for about 1 to 5 hours.

The compound (Ih) is reacted with an oxidizing reagent (e.g.m-chloroperbenzoic acid, etc.) to form the sulfoxide or sulfone compound(Ih′) which is reacted with various nucleophilic reagents (e.g.alcohols, amines, mercaptans, etc.) to give the compound (I) asillustrated in Scheme I″. The oxidation of the compound (Ih) to thesulfoxide or sulfone compound (Ih′) is preferably conducted in solventsincluding halogenated hydrocarbons (e.g. dichloromethane, chloroform,dichloroethane, etc.), ethers (e.g. tetrahydrofuran, dioxane, etc.) andthe like. Examples of such oxidizing reagents include organic peracidssuch as m-chloroperbenzoic acid, N-halosuccinimides such asN-bromosuccinimide, etc. Generally, the oxidizing reagent is employed inan equal or slightly excess amount when compared to the compound (Ih).The sulfoxide can be produced by one mole of the oxidizing reagent andthe sulfone compound (Ih′) by two moles. The reaction is preferablyconducted at temperatures ranging from about ice-cooled temperature toroom temperature for about 3 to 10 hours.

The reaction of the compound (Ih′) into the compound (I) is conducted inessentially the same manner as mentioned in Scheme I′.

The carboxylic acid (Ik) is formed by the alkaline hydrolysis of thecarboxylic acid ester compound (Ij) as illustrated in Scheme J. Thereaction is conducted by using about 1 to 3 mol. of alkali relative to 1mol. of Compound (Ij) usually in a solvent such as an aqueous alcohol(e.g. methanol, ethanol, methyl cellosolve, etc.). Examples of suchalkalis include sodium hydroxide, potassium hydroxide or the like. Thereaction is conducted at temperatures ranging from room temperature toabout 100° C. for about 1 to 10 hours, preferably at about the boilingpoint of a solvent used for about 3 to 5 hours.

The protected tetrazole derivative (Il) is deprotected to give Compound(Im) as depicted in Scheme K. Conditions of the deprotection depend onthe protective group (R) then used. When R is triphenylmethyl,2-tetrahydropyranyl, methoxymethyl, ethoxy methyl or the like, it isconvenient to conduct the reaction in an aqueous alcohol (e.g. methanol,ethanol, etc.) containing about 0.5 N to 2 N hydrochloric acid or aceticacid at about room temperatures for about 1 to 10 hours.

The compound (Iq) is prepared by protecting the tetrazole group in thepresence of a base, and then the carboxyl group to give the estercompound (Ip), followed by removing the protective group under acidconditions as illustrated in Scheme L. In the reaction to obtainCompound (Io) from Compound (In), an alkylating agent is useid in anamount of about 1 to 1.5 mol. relative to 1 mol. of Compound (In).Examples of the solvents to be used for the reaction include halogenatedhydrocarbons such as chloroform, methylene chloride ancd ethylenechloride, ethers such as dioxane and tetrahydrofuran, acetonitrile,pyridine, etc. Examples of such bases include potassium carbonate,sodium carbonate, triethylamine, pyridine, etc. Examples of suchalkylating agents include halides such as triphenylmethyl chloride andmethoxy methyl chloride, etc. While reaction conditions vary withcombinations of the base and the alkylating agent employed, it ispreferable to conduct the reaction by using triphenylmethyl chloride attemperatures ranging from ice-cooling to room temperature for about 1 to3 hours in methylene chloride in the presence of triethylamine. In thereaction for producing Compound (Ip) from Compound (Io) thus obtained,the alkylating agent is used in an amount of about 1 to 3 mol. relativeto 1 mol. of Compound (Iq). Examples of the reaction solvent includeamides such as dimethylformamide and dimethylacetamide, acetonitrile,dimethylsulfoxide, acetone, ethyl methyl ketone, etc. Examples of thebases include potassium carbonate, sodium carbonate, sodium hydride,potassium t-butoxide, etc. Examples of such alkylating agents includehalides such as cyclohexyl 1-iodoethyl carbonate, ethyl 1-iodoethylcarbonate, pivaloyloxymethyl iodide, etc. While reaction conditions varywith combinations of the base and the alkylating agent employed, it ispreferable to subject Compound (Io) to reaction in DMF, by adding thealkylating agent in the presence of potassium carbonate, at about roomtemperatures for about 30 minutes to one hour.

The reaction for deprotecting Compound (Ip) thus obtained is conductedpreferably in a manner similar to the reaction (K). When trityl group isused as the protecting group of tetrazole group, it is preferable toconduct the reaction in methanol or ethanol, while adding 1N—HCl, atabout room temperatures for about 30 minutes to one hour.

The reaction products obtained as above by the reaction processes (A) to(L), can be easily isolated and/or purified by or according toconventional methods such as, for example, evaporation of solvents,extraction by water or organic solvents, concentration, neutralization,recrystallization, distillation, column chromatography and the like. Thecompounds (I) thus produced via the reaction processes as depicted inSchemes A to L can be isolated and/or purified from the reaction mixtureaccording to conventional methods such as, for example,recrystallization and column chromatography, to obtain a crystallineproduct.

The compounds obtained as above by the reaction processes (A) to (L),may be in the form of solvates or salts (including addition salts)derived from pharmaceutically or physiologically acceptable acids orbases. These salts include but are not limited to the following: saltswith inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid and, asthe case may be, such organic acids as acetic acid, oxalic acid,succinic acid, citric acid, ascorbic acid, lact:Lc acid,p-toluenesulfonic acid, methanesulfonic acid, fumaric acid, tartaricacid and maleic acid. Other salts include salts with ammonium, alkalimetals or alkaline earth metals, such as sodium, potassium, calcium ormagnesium or with organic bases (e.g. trialkylaminles, dibenzylamine,ethanolamine, triethanolamine, N-methylmorpholine, etc).

And, by conventional means, the compounds (I) can be formed as saltswith non-toxic, physiologically or pharmaceutically acceptable acids orbases, for example salts with an inorganic acid such as hydrochloride,sulfate or nitrate, and, depending on compounds, salts with an organicacid such as acetate, oxalate, succinate or maleate, salts with analkali metal such as sodium salt or potassium salt, or salts with analkaline earth metal such as calcium salt.

For the synthesis of these compounds (I), the starting compounds (II)and (IV) can be synthesized by or according to the methods described in,for example, the following literature references or methods analogousthereto, namely, by the reactions (M), (N), (O) and (P) as depictedbelow.

(1) P. N. Preston, The Chemistry of Heterocyclic Compounds, Vol. 40, ed.by P. N. Preston, John Wiley & Sons Inc., New York (1981), pp. 1-286,

(2) E. S. Schipper and A. R. Day, Heterocyclic Compounds, Vol. 5, ed. byR. C. Elderfield, John Wiley & Sons Inc., New York (1965), pp. 194-297,

(3) N. J. Leonard, D. Y. Curtin, & K. M. Beck, J. Am. Chem. Soc. 69,2459 (1947),

(4) S. Weiss, H. Michaud, H. Prietzel, & H. Kromer, Angew. Chem. 85, 866(1973),

(5) W. B. Wright, J. Heterocycl. Chem., 2, 41 (1965),

(6) A. M. E. Omar, Synthesis, 1974, 41,

(7) D. J. Brown & R. K. Lynn, J. Chem. Soc.(Perkin I), 1974, 349,

(8) J. A. Van Allan & B. D. Deacon, Org. Syn., 30, 56 (1950),

(9) S. P. Singh, S. S. Parmar & B. R. Pandey, J. Heterocycl. Chem., 14,1093 (1977),

(10) S. Nakajima, I. Tanaka, T. Seki & T. Anmo, Yakugaku Zasshi, 78,1378 (1959),

(11) K. Seno, S. Hagishita, T. Sato & K. Kuriyama, J. Chem. Soc., PerkinTrans. 1984, 2013,

(12) D. R. Buckle et al., J. Med. Chem., 30, 2216 (1987),

(13) R. P. Gupta, C. A. Larroquette & K. C. Agrawal, J. Med. Chem., 25,1342 (1982), etc.

[wherein R², R′, A, X and n are of the same meaning as defined above;and R³ stands for a lower (C₁₋₄) alkyl group].

wherein R², R³, R′, A, Z, X and n are of the same meaning as definedabove.

Schemes M and M′ illustrate the process for preparing importantintermediates which are useful in synthesizing the compound (I) of thepresent invention.

These compounds can be produced according to the above-mentionedreferences. The compound (VI) is converted by the Curtius reaction intothe carbamic acid compound (X) followed by alkylation and subsequentreduction of nitro to form the diamino compound (IV). In therearrangement of Compound (VI) to Compound (X), Compound (X) is producedin a high yield according to conventional procedures of the Curtiusrearrangement: the acid chloride (VII)→the acid azide (VIII)→theisocyanate (IX)→Compound (X). The compound (VI) is conveniently heatedwith diphenylphosphoryl azide (DPPA) in the presence of triethylamine inDMF to form the isocyanate (IX) via the acid azide (VIII) followed byreaction of an alcohol to give the compound (X) in a high yield. Thecompound (X) thus obtained is alkylated in the same manner as in SchemeA to form the compound (XI). In the reaction, it is convenient to heatthe reaction mixture under reflux for about 4-6 hours in the presence ofpotassium carbonate as a base in acetonitrile. The compound (XI) isheated under reflux in an alcohol containing a mineral acid (e.g.hydrochloric acid, sulphuric acid, etc.) or an organic acid (e.g.trifluoroacetic acid, etc.), for about 1-2 hours to give the compound(XII). Various reducing reagents (e.g. raney nickel, stannic chloride,etc.) can be employed in the reduction of the nitro compound (XII) tothe diamino compound (IV). Among them, the combination of ferricchloride and hydrazine·hydrate in an alcohol is the most convenient.Further, the compound (IV) can be prepared by various techniques otherthan those mentioned above.

The compound (X′) commercially available or readily obtained by knownmethods in the art is preferably reacted with the amine (IIIb) in thepresence of a base (e.g. potassium carbonate, sodium carbonate, amines,etc.) in an organic solvent (e.g. alcohol, ethers, halogenatedhydrocarbons, amides, etc.) at temperatures ranging from about theboiling point of the solvent to 100° C. for about 5 to 20 hours.

The compound (X″) readily obtained by acid treatment of the compound (X)is subjected to condensation under dehydration conditions includingazeotropic removal of water (or in the presence of a dehydrating agents)in an organic solvent (e.g. ethers, halogenated hydrocarbons, aromatichydrocarbons, etc.) followed by reaction with a reducing reagent (e.g.NaCNBH₃, etc.) to form the compound (XII). The condensation underdehydration conditions can be accelerated byr using conventional acid orbase catalysts.

The compound (X″) is reacted with the acid chloride (IIId), preferablyin the presence of a base (e.g. pyridine, triethylamine,,dimethylaminopyridine, etc.) in an organic solvent (e.g. halogenatedhydrocarbons, pyridine, etc.) at temperatures ranging from roomtemperature to about the boiling point of the solvent for about 2 to 20hours, to the amide (XI′). The resulting amide (XI′) is reacted with areducing reagent (e.g. sodium aluminum hydride, sodiumbis(2-methoxyethoxy aluminum hydride, etc.) to form the diamino (IV).

[wherein each group is of the same meaning as defined above].

[wherein each group is of the same meaning as defined above].

[wherein each group is of the same meaning as defined above].

And, among the starting compounds (ITT), the compound (III) wherein ndenotes 1, i.e. the compound (IIIa) is commercially available, or can bereadily obtained also by subjecting Compound (XV) to halogenomethylationin accordance with the methods described in literature references, forexample;

1) J. R. E. Hoover, A. W. Chow, R. J. Stedman, N. M. Hall, H. S.Greenberg, M. M. Dolan and R. J. Feriauto, J. Med. Chem., 7, 245 (1964),

2) R. J. Stedman, J. R. E. Hoover, A. W. Chow, M. M. Dolan, N. M. Halland R. J. Feriauto, J. Med. Chem., 7; 251 (1964),

3) H. Gilman and R. D. Gorsich, J. Am. Chem. Soc., 78, 2217 (1956),

4) M. Orchin and E. Oscar Woolfolk, J. Am. Chem. Soc., 67, 122 (1945),etc.

[wherein each group is of the same meaning as defined above].

The compound (IIIa′) can also be readily prepared according to themethods described in L. N. Pridgen, L. Snyoler and J. Prol, Jr., J. Org.Chem., 54, 1523 (1989) as illustrated in Scheme R, followed byhalogenation (R¹²=Me) or halogenomethylation (R¹²=H).

[wherein R¹² is hydrogen or methyl].

Further, among the starting compounds (III), the compound (III) whereinn denotes 2, i.e. the compound (IIIb) can be obtained from the compound(IIIa) in accordance with the reaction (S).

[wherein each group is of the same meaning as defined above].

The compounds and the salts thereof thus produced are less toxic,strongly inhibit the vasoconstrictive and hypertensive actions ofangiotensin II, exert a hypotensive effect in animals, in particularmammals (e.g. human, dog, rabbit, rat, etc.), and therefore they areuseful as therapeutics for not only hypertension but also circulatorydiseases such as heart failure (hypertrophy of the heart, cardiacinsufficiency, cardiac infarction or the like), strokes, cerebralapoplexy, nephropathy and nephritis. The compounds (I) and salts thereofaccording to the present invention strongly inhibit vasoconstriction andhypertension derived by angiotensin II and therefore possess potentanti-hypertensive activity in animals, more specifically mammal animals(e.g. humans, dogs, pigs, rabbits, rats, etc.). Further, the compounds(I) and salts thereof according to the present invention are of quitelow toxicity and clinically useful in treating not only hypertension butalso circulatory system diseases such as heart and brain diseases,strokes, renal failures, nephritiLE and the like.

For therapeutic use, the compounds (I) and salts thereof can be orally,parenterally, by inhalation spray, rectally, or topically administeredas pharmaceutical compositions or formulations (e.g. powders, granules,tablets, pills, capsules, injections, syrups, emulsions, elixirs,suspensions, solutions and the like) comprising at least one suchcompound alone or in admixture with pharmaceutically acceptablecarriers, adjuvants, vehicles, excipients and/or diluents. Thepharmaceutical compositions can be formulated in accordance withconventional methods. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intraperitonealinjections, or infusion techniques. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example, as a solutionin water. Among the acceptable vehicles or solvents that may be employedare water, Ringer's solution, and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil or fatty acidmay be employed including natural, synthetic, or semi-synthetic fattyoils or acids, and natural, synthetic, or semi-synthetic mono-, di-, ortriglycerides.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug. Solid dosage forms for oral administrationmay include powders, granules, tablets, pills, and capsules as mentionedabove. In such solid dosage forms, the active compound may be admixedwith at least one additive such as sucrose, lactose, celluloses,mannitol, maltitol, dextran, starches, agars, alginates, chitins,chitosans, pectins, tragacanth gums, araibic gums, gelatins, collagens,casein, albumin, and synthetic or semi-synthetic polymers or glycerides.Such dosage forms may also comprise, as is normal practice, additionalsubstances other than inert diluents, e.g., lubricating agents asmagnesium stearate, preservatives such as parabens and sorbic acid,antioxidants such as ascorbic acid, α-tocopherol and cysteine,disintegrants, binders, thickening, buffering, sweetening, flavoring,and perfuming agents. Tablets and pills can additionally be preparedwith enteric coatings. Liquid dosage forms for oral administration mayinclude pharmaceutically acceptable emulsions, syrups, elixirs,suspensions, solutions containing inert diluents commonly used in theart, such as water.

Specific dose levels for any particular patient will be employeddepending upon a variety of factors including the activity of specificcompounds employed, the age, body weight, general health, sex, diet,time of administration, route of administration, rate of excretion, drugcombination, and the severity of the particular disease undergoingtherapy. The dose varies with the diseases to be treated, symptoms,subjects and administration routes, and it is desirable that a dailydose of 1 to 50 mg for oral administration or 1 to 30 mg for intravenousinjection is divided into 2 to 3 administrations when used as an agentfor the therapy in adults. For example, when used for treating adultessential hypertension, the active ingredient will preferably beadministered in an appropriate amount, for example, about 10 mg to 100mg a day orally and about 5 mg to 50 mg a day intravenously. The activeingredient will preferably be administered in equal doses two or threetimes a day.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds.

EXAMPLES

By the following formulation examples, working examples, experimentalexamples and reference examples, the present invention will be explainedmore concretely, but they should not be interpreted as limiting theinvention in any manner.

Examples of abbreviations in this specification are as follows:

Me: methyl, Et: ethyl, Tet: tetrazolyl, cycl: cyclo-, Pr: propyl, Bu:butyl, Pen: pentyl, Bu: butyl, Hex: hexyl, Hep: heptyl, Ph: phenyl, DMF:dimethylformamide, and THF: tetrahydrofuran.

Formulation Examples

When the compound (I) of the present invention is used as a therapeuticagent for circulatory failures such as hypertension, heart diseases,strokes, kidney diseases, etc., it can be used in accordance with, forexample, the following formulations.

1. Capsules (1) 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]- 10 mgmethyl]benzimidazole-7-carboxylic acid (2) lactose 90 mg (3) finecrystalline cellulose 70 mg (4) magnesium stearate 10 mg one capsule 180mg

(1), (2), (3) and a half of (4) are mixed and granulated., To thegranules is added the remainder of (4), and the whole is filled intogelatin capsules.

2. Tablets (1) 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]- 10 mgmethyl]benzimidazole-7-carboxylic acid (2) lactose 35 mg (3) corn starch150 mg (4) fine crystalline cellulose 30 mg (5) magnesium stearate 5 mgone tablet 230 mg

(1), (2), (3), two thirds of (4) and a half of (5) are mixed andgranulated. To the granules are added the remainders of (4) and (5),followed by subjecting the granules to compression molding.

3. Injections (1) 2-methylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-10 mg methyl]benzimidazole-7-carboxylic acid disodium salt (2) inositol100 mg (3) benzyl alcohol 20 mg one ampoule 130 mg

(1), (2) and (3) are dissolved in distilled water for injection to makethe whole volume 2 ml, which is filled into an ampoule. The wholeprocess is conducted under sterile conditions.

4. Capsules (1) 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2′-(1H-10 mg tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7- carboxylate(2) lactose 90 mg (3) fine crystalline cellulose 70 mg (4) magnesiumstearate 10 mg one capsule 180 mg

(1), (2), (3) and a half of (4) are mixed and granulated. To thegranules is added the remainder of (4), and the whole is filled intogelatin capsules.

5. Tablets (1) 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2′-(1H- 10mg tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7- carboxylate (2)lactose 35 mg (3) corn starch 150 mg (4) fine crystalline cellulose 30mg (5) magnesium stearate 5 mg one tablet 230 mg

(1), (2), (3), two thirds of (4) and a half of (5) are mixed andgranulated. To the granules are added the remainders of (4) and (5),followed by subjecting the granules to compression molding.

6. Injections (1) 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]- 10mg methyl]benzimidazole-7-carboxylic acid disodium salt (2) inositol 100mg (3) benzyl alcohol 20 mg one ampoule 130 mg

(1), (2) and (3) are dissolved in distilled water for injection to makethe whole volume 2 ml, which is filled into an ampoule. The wholeprocess is conducted under sterile conditions.

Reference Example 1 2-Propoxybenzimidazole

To a solution of o-phenylenediamine (2 g) in propyl orthocarbonate (5ml) was added acetic acid (1.1 ml) and the solution was stirred at 80°C. for 3 hours. To the reaction mixture was added ethyl acetate, and thesolution was washed with an aqueous solution of sodium hydrogencarbonate and water, then dried (Na₂SO₄), followed by concentration todryness. The concentrate was purified by column chromatography on silicagel to give crystals. Recrystallization from ethyl acetate-benzeneafforded colorless crystals (1.54 g, 47%), m.p. 163-164° C.

Reference Example 2 Ethyl 2-carboxy-3-nitrobenzoate

A mixture of 3-nitrophthalic acid (35 g) in ethanol (300 ml) containingconc. sulfuric acid (20 ml) was heated under reflux for 24 hours. Thesolvent was evaporated in vacuo and the residue was poured into coldwater (700 ml). The mixture was extracted with ethyl acetate. Theorganic layer was washed with water and shaken with an aqueous solutionof potassium carbonate. The aqueous layer was made acidic withhydrochloric acid and the mixture was extracted with methylene chloride.The organic layer was washed with water, then dried, followed byevaporation of the solvent. The resultant solid (29 g, 74%) was used forthe subsequent reaction without purification.

¹H-NMR(90 MHz, CDCl₃) δ: 1.43(3H,t), 4.47(2H,q), 7.70(1H,t), 8.40(2H,d),9.87(1H,br s)

IR(Nujol) cm⁻¹: 1725, 1535, 1350, 1300, 1270

Reference Example 3 Ethyl 2-t-butoxycarbonylamino-3-nitrobenzoate

A mixture of ethyl 2-carboxy-3-nitrobenzoate (23.9 g) and thionylchloride (12 ml) in benzene (150 ml) were heated under reflux for 3hours. The reaction mixture was concentrated to dryness. The resultantacid chloride (26 g, quantitative) was dissolved in methylene chloride(20 ml). The solution was added dropwise to a mixture of sodium azide(9.75 g) in dimethylformamide(DMF) (20 ml) with stirring vigorously. Thereaction mixture was poured into a mixture of ether-hexane (3: 1, 200ml) and water (250 ml) to separate into two layers. The organic layerwas washed with water, then dried, followed by evaporation of thesolvent. The residue was dissolved in t-butanol (200 ml) and thesolution was heated gradually with stirring, followed by heating underreflux for 2 hours. The reaction mixture was concentrated in vacuo togive an oily product (30 g).

¹H-NMR(90 MHz, CDCl₃) δ: 1.40(3H,t), 1.53(9H,s), 4.43(2H,q), 7.23(1H,t),8.03-8.27(2H,m), 9.70(1H,br s)

IR(Neat) cm⁻¹: 3320, 2980, 1740, 1585, 1535, 1500, 1440, 1375, 1265,1155

Working Example 1Ethyl-2-[(2′-cyanophenyl-4-yl)methyl]amino-3-nitrobenzoate

To solution of ethyl 2-t-butoxycarbonylamino-3-nitrobenzoate (20 g) intetrahydrofuran (50 ml) was added, while stirring under ice-cooling,sodium hydride (60% dispersion in mineral oil, 2.8 g). The mixture wasstirred at room temperature for 20 minutes and to the mixture were thenadded 4-(2-cyanophenyl)benzyl bromide (18 g) and potassium iodide (360mg), followed by heating for 10 hours under reflux. The solvent wasevaporated to dryness and the residue was partitioned between water (250ml) and ether (200 ml). The organic layer was washed with water, driedand concentrated to give a yellow syrup. The syrup was dissolved in amixture of trifluoroacetic acid (60 ml) and methylene chloride (40 ml)and the solution was stirred for one hour at room temperature. Thereaction mixture was concentrated to dryness and to the residue wasadded ethyl ether (200 ml) to give crystals. The crystals were collectedby filtration, washed with ether to give pale yellow crystals (22.1 g,85%), m.p. 118-119° C.

¹H-NMR(90 MHz,CDCl₃) δ: 1.37(3H,t), 4.23(2H,s), 4.37(2H,q), 6.37(1H,t),7.33-7.83(9H,m), 7.97-8.20(2H,m)

IR(Nujol)cm−1: 3280, 2220, 1690, 1575, 1530, 1480, 1450, 1255, 1105, 755

Working Example 2 Ethyl3-amino-2-[(2′-cyanobiphenyl-4-yl)methyl]aminobenzoate

Dichloride dihydrate (28.1 g) and the mixture was stirred at 80° C. fortwo hours. The solvent was evaporated to dryness. To the ice-coolingmixture of the residue in ethyl acetate (300 ml) was added dropwise 2NNaOH (500 ml) with stirring. The aqueous layer was extracted with ethylacetate (200 ml×2). The organic layers were combined, washed with water,and dried. The solvent was evaporated to dryness and the residue waspurified by column chromatography on silica gel to give crystals.Recrystallization from ethyl acetate-hexane gave colorless crystals (7.3g, 79%), m.p. 104-105° C.

¹H-NMR(200 MHz, CDCl₃) δ: 1.33(3H,t), 4.23(2H,s), 4.27(2H,q),6.83-6.93(2H,m), 7.35-7.55(7H,m), 7.64(1H,dt), 7.76(dd)

IR(KBr) cm⁻¹: 3445, 3350, 2220, 1680, 1470, 1280, 1240, 1185, 1160,1070, 1050, 1020, 805, 750

Working Example 3 Ethyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-methoxybenzimidazole-7-carboxylate

Acetic acid (0.2 g) was added to a solution of ethyl3-amino-2-[(2′-cyanobiphenyl-4-yl)methyl]aminobenzoate (1.1 g) in methylorthocarbonate (5 ml). The mixture was stirred at 80° C. for one hour.The reaction mixture was concentrated, and the concentrate was extractedwith ethyl acetate. The organic layer was then washed with an aqueoussolution of sodium hydrogen carbonate and water. The solvent wasevaporated in vacuo to give crystals. Recrystallization from ethylacetate-benzene afforded colorless crystals (1.09 g, 90%), m.p. 160-161°C.

¹H-NMR(200 MHz, CDCl₃) δ: 1.23(3H,t), 4.23(2H,q), 4.26(3H,s),5.72(2H,s), 7.09(2H,d), 7.20(1H,t), 7.38-7.48(4H,m), 7.58-7.66(2H,m),7.73-7.79(2H,m)

IR(KBr) cm⁻¹ : 3000, 2220, 1725, 1560, 1465, 1440, 1415, 1285, 1250,1220, 1040, 760, 750, 740

Working Example 4 Ethyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate

Acetic acid (0.2 g) was added to a solution of ethyl3-amino-2[(2′-cyanobiphenyl-4-yl)methyl]aminobenzoate (1.0 g) in ethylorthocarbonate (5 ml).. The mixture was stirred at 80° C. for one hour.The reaction mixture was concentrated, and the concentrate was dissolvedin ethyl acetate. The solution was washed with an aqueous solution ofsodium hydrogen carbonate and water. The solvent was evaporated to givecrystals. Recrystallization from ethyl acetate-benzene affordedcolorless crystals (0.79 g, 69%), m.p. 131-132° C. Elemental Analysisfor C₂₆,H₂₃N₃O₃:

C (%) H (%) N (%) Calcd.: 73.39; 5.45; 9.88 Found: 73.36; 5.42; 9.83

¹H-NMR(20 MHz, CDCl₃) δ: 1.24(3H,t), 1.49(3H,t), 4.24(2H,q), 4.68(2H,q),5.72(2H,s), 7.10(2H,d), 7.19(1H,t), 7.38-7.46(4H,m), 7.56-7.66(2H,m),7.73-7.77(2H,m)

IR(KBr) cm⁻¹: 2220, 1720, 1550, 1480, 1430, 1280, 1245, 1215, 1040, 760,740

Working Example 5 Ethyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-propoxybenzimidazole-7-carboxylate

Acetic acid (0.2 g) was added to a solution of ethyl3-amino-2-[(2′-cyanobiphenyl-4-yl)methyl]aminobenzoate (0.9 g) in propylorthocarbonate (5 ml). The mixture was stirred at 80° C. for one hour.The reaction mixture was concentrated, and the concentrate was dissolvedin ethyl acetate. The solution was washed with an aqueoues solution ofsodium hydrogen carbonate. The solvent was evaporated to give crystals.Recrystallization from ethyl acetate-benzene afforded colorless crystals(0.72 g, 68%), m.p. 90-92° C. Elemental Analysis for C₂₇H₂₅N₃O₃:

C (%) H (%) N (%) Calcd.: 73.79; 5.73; 9.56 Found: 73.84; 5.79; 9.54

¹H-NMR(200 MHz, CDCl₃) δ: 1.01(3H,t), 1.25(3H,t), 1.80-1.97 (2H,m),4.24(2H,q), 4.57(2H,q), 5.72(2H,s), 7.11(2H,d), 7.19(1H,t),7.38-7.46(4H,m), 7.56-7.66(2H,m), 7.73-7.77(2H,m)

IR(KBr) cm⁻¹: 2220, 1725, 1550, 1480, 1460, 1430, 1370, 1280, 1245,1210, 1115, 1040, 760, 750, 740

Working Example 6

Ethyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-mercaptobenzimidazole-7-carboxylate

A mixture of ethyl3-amino-2-[(2′-cyanobiphenyl-4-yl)-methyl]aminobenzoate (5.6 g) andsodium O-ethyl dithiocarbonate (7.3 g) in ethanol (50 ml) was heated for8 hours under reflux. The reaction mixture was concentrated and theresidue was dissolved in water. The solution was adjusted to pH 3-4 withhydrochloric acid. Precipitating crystals were collected by filtration,followed by recrystallization from ethanol to afford yellow crystals(5.0 g, 80%), m.p. 225-227° C.

¹H-NMR(200 MHz, DMSO-d₆) δ: 1.08(3H,t), 4.12(2H,q), 5.90(2H,brs),7.08(2H,d), 7.27(1H,t), 7.38-7.59(6H,m), 7.76(1H,dt), 7.92(1H,dd)

IR(KBr) cm⁻¹: 2210, 1720, 1460, 1440, 1420, 1375, 1335, 1265, 1180,1135, 1115, 1100, 985, 760, 740

Reference Example 4 Methyl2-[[(2′-cyanobiphenyl)methyl]amino]-3-nitrobenzoate

A mixture of ethyl 2-[[(2′-cyanobiphenyl)methyl]amino]-3-nitrobenzoate(5 g) and sodium hydride (60% dispersion in mineral oil, 1.62 g) inmethanol (50 ml) was stirred at room temperature for one day. Thereaction mixture was concentrated and the residue was poured into asaturated aqueous solution of sodium hydrogen carbonate (100 ml),followed by extraction with chloroform. The organic layer was washedwith water, dried and concentrated to dryness to give crystals.Recrystallization from ethyl acetate-hexane afforded pale yellowcrystals (3.98 g, 83%), m.p. 106-108° C.

¹H-NMR(200 MHz, CDCl₃) δ: 3.81(3H,s), 3.97(2H,br s), 4.23(2H,s),6.40(1H,br s), 6.88-6.91(2H,m), 7.34-7.55(7H,m), 7.65(1H,dt,J=1.2, 7.7Hz), 7.77(1H,dd,J=1.4,8.0 Hz)

IR(KBr) cm⁻¹: 3410, 3350, 2225, 1695, 1485, 1470, 1290, 1200, 780, 760

Working Example 7 Methyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate

Acetic acid (0.37 g) was added to a solution of methyl3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]benzoate (2.03 g) inethyl orthocarbonate (5 ml), and the mixture was stirred at 80° C. forone hour. The reaction mixture was concentrated to dryness and theresidue was dissolved in ethyl acetate. The solution was washed with anaqueous solution of sodium hydrogen carbonate and water. The solvent wasevaporated in vacuo to give crystals. Recrystallization from ethylacetate-hexane afforded colorless crystals (2.01 g, 86%), m.p.168.5-169.5° C.

Elemental Analysis:

C (%) H (%) N (%) Calcd.: 72.98; 5.14; 10.21 Found: 72.71; 5.12;  9.97

¹H-NMR(200 MHz,CDCl₃) δ: 1.42(3H,t,J=7.1 Hz), 3.71(3H,s),4.63(2H,q,J=7.1 Hz), 5.59(2H,s), 7.09(2H,d,J=8.4 Hz), 7.20(1H,t,J=7.9Hz), 7.45-7.59(5H,m), 7.69-7.80(2H,m), 7.92(1H,dd,J=1.4,7.8 Hz)

IR(KBr) cm⁻¹: 2225, 1725, 1550, 1480, 1430, 1350, 1280, 1250, 1040, 760,750

Reference Example 5 Ethyl2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-(3-ethylthioureido)benzoate

A mixture of ethyl3-amino-2-[[(2′-cyanobiphenyl-4-yl)-methyl]amino]benzoate (1.61 g),ethyl isothiocyanate (1.5 ml) and ethanol (1 ml) was stirred at roomtemperature for 3 days. The reaction mixture was dissolved in ethylacetate and the solution was washed with water, dried and concentratedto dryness to give crystals. Recrystallization from ethyl acetate-hexaneafforded pale yellow crystals (1.92 g, 91%), m.p. 108-110° C.

¹H-NMR(200 MHz,CDCl₃) δ: 1.15(3H,t), 1.40(3H,t), 3.50-3.70(2H,brs),4.37(2H,q), 4.56(2H,d), 6.07(1H,t), 6.78(1H,t), 7.19-7.24(1H,m),7.38-7.53(6H,m), 7.63(1H,dt), 7.72-7.76(1H,m), 7.99(1H,dd), 8.29(1H,brs)

IR(KBr) cm⁻¹: 3375, 3320, 3150, 2975, 2220, 1740, 1680, 1540, 1510,1450, 1300, 1225, 1180, 1150, 760, 750

Reference Example 6 Ethyl2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-(3-propylthioureido)benzoate

In substantially the same manner as Reference Example 5, desired paleyellow syrup (2.0 g, 98%) was obtained from ethyl3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]benzoate (1.6 g), propylisothiocyanate (1.5 ml) and ethanol (1 ml).

¹H-NMR(200 MHz,CDCl₃) δ: 0.88(3H,t), 1.40(3H,t), 1.48-1.67(2H,m),3.42-3.68(2H,br s), 4.37(2H,q), 4.56(2H,d), 6.13(1H,t), 6.78(1H,t),7.21-7.25(1H,m), 7.36-7.53(6H,m), 7.64(1H,dt), 7.73-7.77(1H,m),7.99(1H,dd), 8.20-8.40(1H,br s)

IR(Neat)cm⁻¹: 3325, 3175, 2960, 2930, 2875, 2220, 1710, 1690, 1590,1475, 1360, 1175, 1140, 1090, 1020, 760

Working Example 8 Ethyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethylaminobenzimidazole-7-carboxylate

Methyl iodide (4.5 g) was added to a solution of ethyl2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-(ethylthioureido)benzoate(1.8 g) in ethanol (50 ml), and the mixture was heated under reflux for12 hours. To the reaction mixture was added 1N-HCl (60 ml) and themixture was stirred at room temperature for 30 minutes. The reactionmixture was concentrated to dryness and the concentrate was dissolved inethyl acetate. The solution was washed with an aqueous solution ofsodium hydrogen carbonate and water and dried. The solvent wasevaporated to dryness and the residue was purified by columnchromatography on silica gel to afford yellow syrup (0.96 g, 58%).

¹H-NMR(200 MHz,CDCl₃) δ: 1.23(6H,t), 3.48-3.62(2H,m), 4.09(1H,t),4.23(2H,q), 5.57(2H,s), 7.15(1H,t), 7.25(2H,d), 7.40-7.77(8H,m)

IR(Neat)cm⁻¹: 3400, 3225, 2975, 2930, 2210, 1710, 1610, 1570, 1480,1425, 1365, 1320, 1270, 1250, 1210, 1130, 1100, 1060, 770, 750

Working Example 9 Ethyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-propylaminobenzimidazole-7-carboxylate

In substantially the same manner as Working Example 8, desired yellowsyrup (1.2 g, 65%) was obtained from a solution of ethyl2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-(3-propylthioureida)-benzoate(2.0 g) and methyl iodide (4.8 g) in ethanol (50 ml).

¹H-NMR(200 MHz,CDCl₃) δ: 0.87(3H,t), 1.25(6H,t), 1.52-1.70(2H,m),3.42-3.52(2H,m), 4.12(1H,t), 4.25(2H,q), 5.58(2H,s), 7.16(1H,t),7.29(2H,d), 7.41-7.78(8H,m)

IR(Neat)cm⁻¹: 3400, 3250, 2975, 2950, 2890, 2225, 1715, 1620, 1590,1570, 1480, 1430, 1370, 1285, 1220, 1135, 1070, 760

Working Example 10 Methyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-methoxybenzimidazole-7-carboxylate

A solution of 5.2 M sodium methoxide in methanol (0.5 ml) was added to asolution of ethyl1-[(2′-cyanobiphenyl-4-yl)methyl]2-methoxybenzimidazole-7-carboxylate(1.3 g) in methanol (50 ml). The mixture was heated for 4 hours underreflux. The reaction mixture was concentrated, and the precipitatedcrystals were collected by filtration. Recrystallization from methanolafforded colorless prisms (1.1 g, 85%), m.p. 149-150° C.

Elemental Analysis for C₂₄H₁₉N₃O₃:

C (%) H (%) N (%) Calcd.: 72.53; 4.82; 10.57 Found: 72.38; 4.93; 10.44

¹H-NMR(200 MHz,CDCl₃) δ: 3.75(3H,s), 4.26(3H,s), 5.69(2H,s), 7.09(2H,d),7.23(1H,t), 7.37-7.46(3H,m), 7.55-7.65(2H,m), 7.72-7.78(2H,m)

Reference Example 7 Methyl2-[[(2′-cyanobiphenyl-4-yl)]methyl]amino-3-(3-methylthioureido)benzoate

The above compound was synthesized (86% yield) in substantially the samemanner as Reference Example 5.

m.p. 152-155° C.

¹H-NMR(200 MHz,CDCl₃) δ: 3.05-3.07(3H,br s), 3.92(3H,s), 4.58(2H,d),6.04-6.08(1H,br s), 6.77(1H,t), 7.22-7.26(1H,m), 7.39-7.52(6H,m),7.63(1H,dt), 7.75(1H,dd), 7.97(1H,dd), 8.28(1H,br s)

IR(KBr) cm⁻¹: 3375, 3325, 3175, 2220, 1680, 1590, 1540, 1500, 1480,1450, 1435, 1265, 1230, 1190, 1145, 1050, 830, 760, 740

Working Example 11 Methyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-methylaminobenzimidazole-7-carboxylate

The above compound was synthesized as a syrup (42% yield) insubstantially the same manner as Working Example 8.

¹H-NMR(200 MHz,CDCl₃) δ: 3.11(3H,d), 3.73(3H,s), 4.22(1H,q), 5.54(2H,s),7.17(1H,t), 7.27(2H,d), 7.41-7.79(8H,m)

IR(Neat)cm⁻¹: 3400, 3250, 3025, 2950, 2220, 1720, 1625, 1610, 1580,1480, 14110, 13340, 1280, 1240, 1210, 1130, 1060, 750

Reference Example 82-Propoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole

Sodium hydride (60% dispersion in mineral oil, 0.24 g) was added to astirred solution of 2-propoxybenzimidazole (0.71 g) in DMF (10 ml) underice-cooling. The mixture was stirred for 20 minutes, to which was addedN-triphenylmethyl-5-[2-(4-bromomethylbiphenyl]-tetrazole (2.3 g),followed by stirring at room temperature for 5 hours. To the reactionmixture was added ice-water, the mixture was extracted with ethylacetate. The organic layer was washed with water, dried and concentratedto dryness. The concentrate was dissolved in methanol (50 ml), to whichwas added 1N-HCl (15 ml), followed by stirring at 60° C. for 2 hours.The reaction mixture was concentrated, to which were added water (15 ml)and ethyl acetate (15 ml). The mixture was made alkaline with 1N NaOHand shaken. The aqueous layer was adjusted to pH 3-4 with 1N-HCl andthen extracted with chloroform. The organic layer was washed with water,dried and concentrated to dryness. The concentrate was purified bycolumn chromatography on silica gel to yield crystals. Recrystallizationfrom ethyl acetate-methanol gave colorless crystals (0.58 g, 35%), m.p.177-179° C. (decomp.).

Elemental Analysis for C₂₄H₂₂N₆O:

C (%) H (%) N (%) Calcd.: 70.23; 5.40; 20.47 Found: 69.93; 5.43; 20.22

¹H-NMR(200 MHz,DMSO-d₆) δ: 0.95(3H,t), 1.70-1.88(2H,m), 4.46(2H,t),5.23(2H,s), 7.04-7.10(4H,m), 7.20(2H,d), 7.38-7.43(2H,m),7.48-7.70(4H,m)

IR(KBr) cm⁻¹: 1540, 1535, 1485, 1475, 1450, 1425, 1385, 1285, 1270,1040, 980, 755, 745

Working Example 12 Methyl2-butylamino-1-[(2′-cyanobiphenyl-4-yl)methyl]-benzimidazole-7-carboxylate

The title compound was prepared from methyl2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-(butylureido)benzoate insubstantially the same manner as Working Example 8. The yield wasquantitative.

¹H-NMR(200 MHz,CDCl₃) δ: 0.89(3H,t), 1.21-1.39(2H,m), 1 .45-1.60(2H,m),3.50-3.65(3H,brs), 3.92(3H,s), 4.56(2H,d), 6.08(1H,t), 6.78(1H,t),7.21-7.30(1H,m), 7.39-7.54(6H,m), 7.64(1H,dt), 7.75(1H,dd), 7.98(1H,dd),8.26(1H,brs)

Working Example 13 Methyl2-(N-ethylmethylamino)-1-[(2′-cyanobiphenyl-4-yl)-methyl]benzimidazole-7-carboxylate

A mixture of sodium hydride (60% dispersion in mineral oil, 0.13 g) inDMF (5 ml) was stirred under ice-cooling for 5 min. and methyl2-ethylamino-1-[(2′-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate(0.95 g) was added to the mixture, followed by stirring for 10 min. Tothe mixture was added methyl iodide (0.2 ml) and the mixture was stirredfor 20 min. To the reaction mixture was added water and the mixture wasextracted with ethyl acetate. The extract was washed with water, driedand evaporated to dryness. The residue was purified by columnchromatography on silica gel to give crude cristals, which wererecrystallized from ethyl acetate-hexane to afford colorless needles(0.88 g, 82%), m.p. 66-69° C.

¹H-NMR(200 MHz,CDCl₃) δ: 1.25(3H,tI, 3.03(3H,s), 3.36(2H,q), 3.73(3H,s),5.60(2H,s), 6.88(2H,d), 7.16(1H,t), 7.34-7.49(5H,m), 7.59(1H,dt),7.73(1H,dd), 7.78(1H,dd)

IR(KBr) cm⁻¹: 2210, 1710, 1540, 1530, 1435, 1420, 1385, 1300, 1275,1250, 1005, 760

Reference Example 9 Methyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-oxo-2,3-dihydrobenzimidazole-7-carboxvlate

To a solution of methyl2-[(2′-cyanobiphenyl-4-yl)-methylamino]-3-methoxycarbonylaminobenzoate(10.5 g) in methanol (100 ml) was added NaOMe (10 g), and the mixturewas heated under reflux for 20 hours. The reaction mixture wasneutralized with 1N-HCl and concentrated to dryness. The residue wasextracted with chloroform-water. The organic layer was washed withwater, dried and evaporated to dryness. The resulting crystals wererecrystallized from chloroform-methanol to afford colorless needles(8.67 g, 89%), m.p. 250-253° C.

¹H-NMR(200 MHz,DMSO-d₆) δ: 3.65(3H,s), 5.35(2H,s), 7.04-7.16(3H.m),7.24-7.28(2H,m), 7.48-7.59(4H,m), 7.76(1H,dt), 7.92(1H,dd)

IR(KBr) cm⁻¹: 2210, 1720, 1690, 1635, 1430, 1390, 1270, 1255, 760, 750,730, 690

Reference Example 10 Methyl2-chloro-1-[(2′-cyanobiphenyl-4-yl)methyl]-benzimidazole-7-carboxylate

A mixture of methyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-oxo-2,3-dihydrobenzimidazole-7-carboxylate(8.02 g) in phosphorus oxychloride (30 ml) was heated under reflux for 8hours. The reaction mixture was concentrated and the resulting residuewag poured into ice-water. The mixture was extracted with chloroform.The extract was washed with water, dried and evaporated. The residue waspurified by column chromatography on silica gel to give crystals, whichwere recrystallized from chloroform-methanol to afford colorless needles(2.2 g, 28%), m.p. 154-157° C.

¹H-NMR(200 MHz,CDCl₃) δ: 3.78(3H,s), 5.95(2H,s), 7.06(2H,d), 7.31(1H,t),7.39-7.48(4H,m), 7.58-7.66(1H,m), 7.71-7.77(2H,m), 7.93(1H,dd)

IR(KBr) cm⁻¹: 2240, 1720, 1480, 1450, 1440, 1425, 1370, 1350, 1290,1270, 1200, 1150, 1120, 1000, 775, 760, 750

Reference Example 11 Methyl2-[(2′-cyanobiphenyl-4-yl)methylamino]-3-methoxycarbonylaminobenzoate

To a stirred solution of methyl3-amino-2-[(2′-cyanobiphenyl-4-yl)methylamino]benzoate (10 g) inpyridine (50 ml) was added dropwise methyl chloroformate (9.0 ml) underice-cooling. The mixture was stirred at room temperature for 3 hours andconcentrated. The residue was extracted with ethyl acetate. The extractwas washed with water, dried and evaporated. The residue wasrecrystallized from ethyl acetate-hexane to afford pale yellow needles(10.5 g, 90%), m.p. 113-115° C.

¹H-NMR(200 MHz,CDC₃) δ: 3.80(3H,s), 3.83(3H,s), 4.11(2H,d),6.29(1H,brs), 7.09(1H,t), 7.40-7.80(10H,m), 8.19(1H,d)

Working Example 14 Methyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-morpholinobenzimidazole-7-carboxylate

A mixture of methyl2-chloro-1-[(2′-cyanobiphenyl-4-yl)-methyl]benzimidazole-7-carboxylate(0.8 g) in morpholine (15 ml) was stirred at 100° C. for 2 hours and thereaction mixture was concentrated to dryness. The residue was extractedwith ethyl acetate. The extract was washed with water, dried andevaporated. The resulting crystals were recrystallized from ethylacetate-hexane to afford colorless prisms (0.69 g, 77%).

¹H-NMR(200 MHz,CDCl₃) δ: 3.38(4H,t), 3.72(3H,s), 3.90(4H,t), 5.63(2H,s),6.89(2H,d), 7.20(1H,t), 7.37-7.65(6H,m), 7.74(1H,dd), 7.82(1H,dd)

IR(KBr) cm⁻¹: 2225, 1715, 1520, 1440, 1415, 1280, 1260, 1220, 1130,1120, 1010, 860, 770, 760, 750

Working Example 15 Methyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-piperidinobenzimidazole-7-carboxylate

The title compound was prepared in substantially the same manner asWorking Example 14. Yield: 81%, m.p. 119-121° C.

¹H-NMR(200 MHz,CDCl₃) δ: 1.62-1.77(6H,m), 3.31-3.36(4H,m), 3.73(3H,s),5.58(2H,s), 6.88(2H,d), 7.15(1H,t), 7.35-7.49(5H,m), 7.56-7.64(1H,m),7.73(1H,dd), 7.79(1H,dd)

IR(KBr) cm⁻¹: 2225, 1720, 1530, 1445, 1410, 1385, 1305, 1285, 1265,1250, 1130, 1110, 770, 750

Reference Example 12 Methyl2-[(2′-methoxycarbonylbiphenyl-4-yl)methylamino]-3-nitrobenzoate

To a solution of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (1.84g) in acetonitrile (10 ml) was added a solution of4-(2′-methoxycarbonylbiphenyl-4-yl)methyl bromide (1.9 g) inacetonitrile (5 ml) and potassium carbonate (0.86 g) and the reactionmixture was heated under reflux for 20 hours. The reaction mixture wasconcentrated to dryness and the resulting residue was extracted withethyl acetate and water. The organic layer was washed with water, driedand evaporated. The residue was purified by column chromatography onsilica gel to give pale yellow syrup. The syrup was dissolved in ethanol(10 ml) and 20% hydrochloric acid in ethanol (4 ml) was added to thesolution. The reaction mixture was stirred at room temperature for 22hours and concentrated to dryness. The residue was dissolved in ethylacetate and the solution was washed with saturated aqueous sodiumbicarbonate and water, dried and evaporated to afford yellow syrup (1.39g, 53%).

¹H-NMR(200 MHz,CHCl₃) δ: 3.61(3H,s), 3.89(3H,s), 4.21(2H,d), 6.72(1H,t),7.30(4H,d), 7.36(1H,dd), 7.42(1H,dd), 7.53(1H,dd), 7.82(1H,dd),8.00(1H,dd), 8.10(1H,dd)

Reference Example 13 Methyl3-amino-2-[(2′-methoxycarbonylbiphenyl-4-yl)methylamino]benzoate

The title compound was prepared as pale yellow syrup from methyl2-[(2′-methcxycarbonylbiphenyl-4-yl)methylamino]-3-nitrobenzoate insubstantially the same manner as Working Example 2. Yield: 79%.

¹H-NMR(200 MHz,CHCl₃) δ: 3.63(3H,s), 3.80(3H,s), 3.97(2H,brs),4.22(2H,d), 6.40(1H,brs), 6.82-6.92(2H,m), 7.23-7.44(7H,m), 7.53(1H,dt),7.79-7.83(1H,m)

IR(Neat) cm⁻¹: 3450, 3360, 2970, 1730, 1700, 1470, 1460, 1450, 1440,1290, 1250, 1200, 770, 750

Working Example 16 Methyl 2-ethoxy-1- [(2′-methoxycarbonylbiphenyl-4-yl)methyl]benzimidazole-7-carboxylate

The title compound was prepared as colorless plates from methyl3-amino-2-[(2′-methoxycarbonylbiphenyl-4-yl)methylamino]-benzoate insubstantially the same manner as Working Example 4. Yield: 72%, m.p.112-113° C.

¹H-NMR(200 MHz,CHCl₃) δ: 1.50(3H,t), 3.55(3H,s), 3.77(3H,s), 4.68(2H,q),5.65(2H,s), 6.99(2H,d), 7.17(2H,d), 7.17(1H,t), 7.31-7.55(4H,m),7.73(1H,dd), 7.77(1H,dd)

IR(Neat)cm⁻¹: 1730, 1710, 1545, 1470, 1430, 1380, 1340, 1320, 1270,1250, 1235, 1210, 1120, 1080, 1030, 750, 740, 710

Working Example 17 Methyl2-butoxy-1-[(2′-cyanobiphenyl-4-yl)methyl]benzimidazole7-carboxylate

The title compound was prepared as colorless needles in substantiallythe same manner as Working Example 7.

Yield: 75%, m.p. 74-75° C.

¹H-NMR(200 MHz,CDCl₃) δ: 0.95(3H,t), 1.35-1.54(2H,m), 1.77-1.90(2H,m),3.76(3H,s), 4.60(2H,t), 5.69(2H,s), 7.10(2H,d), 7.17(1H,t), 7.43(4H,d),7.54-7.65(2H,m), 7.74(2H,dd)

IR(KBr) cm⁻¹: 2220, 1725, 1560, 1490, 1470, 1440, 1395, 1320, 1295,1265, 1245, 1120, 1050, 1020, 770

Working Example 18 Methyl2-allyloxy-1-[(2′-cyanobiohenyl-4-yl)methyl]benzimidazole-7-carboxylate

The title compound was prepared as colorless plates in substantially thesame manner as Working Example 7.

Yield: 73%, m.p. 118-119° C.

¹H-NMR(200 MHz,CDCl₃) δ: 3.76(3H,s), 5.12(2H,m), 5.33(1H,m), 5.43(1H,m),5.72(2H,s), 6.02-6.21(1H,m), 7.11(2H,d), 7.19(1H,t), 7.44(4H,d),7.56-7.66(2H,m), 7.75(2H,dd)

IR(KBr) cm⁻¹: 2220, 1705, 1540, 1470, 1460, 1425, 1410, 1400, 1330,1300, 1270, 1 250, 1225, 1205, 1100, 1015, 995, 760, 750, 740, 730

Working Example 19 Methyl2-ethylamino-1-[(2′-cyanobiphenyl-4-yl)methyl]-benzimidazole-7-carboxylate

The title compound was prepared as colorless crystals (3.2 g, 32%)according to the procedure for Working Example 8 from methyl2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-(3-ethylthioureido)benzoate(10.5 g), which was synthesized from methyl3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]benzoate insubstantially the same manner as Reference Example 5.

¹H-NMR(200 MHz,CDCl₃) δ: 1.24(3H,t), 3.49-3.63(2H,m), 4.06(1H,t),5.55(2H,s), 7.16(1H,t), 7.27(2H,d), 7.41-7.79(8H,m)

IR(KBr) cm⁻¹: 3275, 2225, 1720, 1620, 1610, 1580, 1570, 1480, 1350,1275, 1240, 1215, 1100, .1070, 770, 760

Working Example 20 2-Cyano-4′-methylbiphenyl

20a) N-(2-Methoxyphenyl)methylidenecyclohexylamine

A solution of anisaldehyde (21 g) and cyclohexylamine (15 g) inchloroform. (100 ml) was stirred at room temperature for 2 hours andevaporated to afford brown syrup (35 g, quantitative).

¹H-NMR(200 MHz,CDCl₃) δ: 1.21-1.87(10H,m), 3.14-3.28(1H,m), 3.86(3H,s),6.88-7.00(2H,m), 7.36(1H,m), 7.95(2H,dd), 8.75(1H,s)

20b) 4′-Methyl-2-biphenylcarbaldehyde

To a suspension of magnesium metal (1.1 g) in THF (3 ml) was addeddropwise a solution of 4-bromotoluene (7.5 g) in THF (10 ml) undergentle reflux. The resulting solution of the Grignard reagent was addeddropwise to an ice-cooled, stirred solution ofN-(2-methoxyphenyl)methylidenecyclohexylamine (4.3 g) in THF (30 ml).The reaction mixture was stirred at room temperature for 1.5 hours,followed by heating under reflux for 7 hours. After addition ofice-water, the reaction mixture was acidified with conc. hydrochloricacid. The reaction mixture was extracted with ethyl acetate and theextract was washed with 1N-hydrochloric acid and water, dried andevaporated to dryness. The residue was purified by column chromatographyon silica gel to give pale yellow syrup (2.0 g, 51%).

¹H-NMR(200 MHz,CDCl₃) δ: 2.43(3H,s), 7.28(4H,s), 7.42-7.51(2H,m),7.63(1H,t), 8.02(1H,d), 10.00(1H,s)

20c) 2-Cyano-4′-methyibiphenyl

A mixture of 4′-methyl-2-biphenylcarbaldehyde (2.0 g) and hydroxyaminehydrochloride (1.0 g) in pyridine (10 ml) was stirred at roomtemperature for 15 min., followed by addition of acetic anhydride (4.1g). The reaction mixture was stirred at 90-100° C. for 1 hr. andconcentrated to dryness. After addition of water to the residue, theprecipitated crystals were collected by filtration. Recrystallizationfrom hexane gave colorless needles (1.5 g, 79%).

¹H-NMR(90 MHz,CDCl₃) δ: 2.40(3H,s), 7.2-7.8(8H,m)

The title compound can be readily converted into Compoud (IIIa′)according to the known references as mentioned above.

Working Example 21 Methyl 2-carboxy-3-nitrobenzoate

To a suspension of 3-nitrophthalic acid (211 g) and methyl orthoformate(127 g) in methanol (420 ml) was added conc. sulfuric acid (20 ml)dropwise with stirring. The reaction mixture was heated under reflux for18 hours and concentrated to dryness. After addition of water (30 ml) tothe residue, the mixture was stirred at 3-10° C. for one hour. Theprecipitated crystals were recrystallized from ethyl acetate-hexane togive pale yellow prisms (185 g, 82%), m.p. 166-168° C.

¹H-NMR(200 MHz, CDCl₃) δ: 4.03(3H,s), 7.74(1H,t), 8.39(1H,dd),8.42(1H,dd)

Working Example 22 Methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate

To a solution of methyl 2-carboxy-3-nitrobenzoate (7.23 g) in DMF (50ml) was added diphenylphosphoryl azide (11.3 g) at room temperature andthen triethylamine (6.7 ml) was added dropwise to the stirred reactionmixture. After stirring at room temperature for 3 hours, tert-butanol(54 ml) was added to the stirred reaction mixture. After stirring atroom temperature for 30 min., the reaction mixture was gradually warmed,then heated under reflux for 1 hour and evaporated to dryness. Theresultant residue was dissolved in ethyl acetate, washed with dilutehydrochloric acid, aqueous sodium bicarbonate, and water, and thendried. After evaporation of the solvent, methanol was added to theresultant residue and the mixture was cooled to give colorless crystals(6.7 g, 70%).

¹H-NMR(200 MHz, CDCl₃) δ: 1.50(9H,s), 3.96(3H,s), 7.23(1H,t),8.10(1H,dd), 8.17(1H,dd)

IR(KBr) cm⁻¹: 3360, 1730, 1705, 1580, 1520, 1490, 1440, 1365, 1355,1310, 1270, 1240, 1150, 870, 835, 770, 725, 705

Working Example 23 Methyl2-[[N-tert-butoxycarbonyl-N-(2′-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate

A solution of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (0.6 g),2-(4-bromomethylphenyl)benzonitrile (0.54 g) and K₂CO₃ (0.28 g) inacetonitrile (10 ml) was heated under reflux for 4 hours andconcentrated to dryness. Water was added to the resultant residue andthe mixture was extracted with ethyl acetate. The extract was washedwith water, dried and evaporated to dryness. The residue was purified bycolumn chromatography on silica gel to give crystals. Recrystallizationfrom ethyl acetate-hexane afforded colorless prisms (0.83 g, 85%), m.p.153-154° C.

¹H-NMR(200 MHz,CDCl₃) δ: 1.35(9H,s), 3.70(3H,s), 4.63(1H,d), 4.80(1H,d),7.23-7.29(3H,m), 7.39-7.53(6H,m), 7.59-7.67(1H,m), 7.75(1H,dd),7.93(1H,dd), 7.99(1H,dd), 8.05(1H,dd), 8.11(1H,dd)

IR(KBr) cm⁻¹: 2220, 1700, 1530, 1390, 1360, 1315, 1290, 1160, 765

Working Example 24 Methyl2-[[2′-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate

A mixture of methyl2-[[N-tert-butoxycarbonyl-N-(2′-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate(0.49 g) in 20% HCl-ethanol (3 ml) and ethyl acetate (3 ml) was stirredat room temperature for 1 hour. After evaporation of the solvent, to theresidue was added methanol and saturated aqueous sodium bicarbonate togive crystals. The crystals were collected by filtration andrecrystallized from chloroform-methanol to give pale yellow crystals(0.3 g, 77%), m.p. 140-141° C.

¹H-NMR(200 MHz, DMSO-d₆) δ: 3.84(3H,s), 4.26(2H,m), 6.86(1H,t),7.46(2H,d), 7.54-7.65(4H,m), 7.79(1H,d), 7.95(dd), 8.05-8.11(2H,m),8.67(1H,t)

Working Example 25 Methyl3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]benzoate

A mixture of methyl2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate (10 g),FeCl₃.6H₂O (0.1 g), activated charcoal (1 g) in a mixture of methanol(100 ml) and THF (50 ml) was heated under reflux for 30 min. Hydrazinehydrate (7.2 ml) was added dropwise to the reaction mixture and themixture was then heated under reflux for 14 hours. The insolublematerial was removed from the reaction mixture by filtration and thefiltrate was concentrated to dryness. Aqueous sodium bicarbonate wasadded to the resulting residue and the mixture was extracted with ethylacetate. The extract was washed with water, dried and evaporated todryness. The residue was purified by column chromatography on silica gelto give crystals. Recrystallization from isopropyl ether afforded paleyellow needles (6.0 g, 64%), m.p. 110-111° C.

¹H-NMR(200 MHz,CDCl₃) δ: 3.81(3H,s), 3.97(2H,brs), 4.23(2H,d),6.39(1H,t), 6.84-6.93(2H,m), 7.26-7.55(8H,m), 7.64(1H,dt), 7.77(1H,dd)

Working Example 26 Methyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-(2,2,2-trifluoroethoxy)benzimidazole-7-carboxylate

The title compound was prepared as pale yellow crystals from methyl3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]benzoate and2,2,2-trifluoroethyl orthocarbonate according to the procedure forWorking Example 3. Yield: 25%, m.p. 143-145° C.

Elemental Analysis for C₂₅H₁₈F₃N₃O₃:

C (%) H (%) N (%) Calcd.: 64.52; 3.90; 9.03 Found: 64.35; 3.95; 8.98

¹H-NMR(200 MHz,CDCl₃) δ: 3.80(3H,s), 5.01(2H,q), 5.74(2H,s), 7.13(2H,d),7.23(1H,t), 7.38-7.47(4H,m), 7.58-7.66(2H,m), 7.72-7.78(2H,m)

IR(KBr) cm⁻¹: 2225, 1735, 1550, 1465, 1430, 1305, 1280, 1270, 1250,1170, 1060, 770, 750, 745

Working Example 27 Ethyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole7-carboxylate

To a solution of ethyl2-chloro-1-[(2′-cyanobiphenyl-4-yl)-methyl]benzimidazole-7-carboxylate(1.0 g) in ethanol (30 ml) was added NaOEt (0.17 g) and the mixture washeated under reflux for 1 hour. The reaction mixture was concentrated todryness. The resultant residue was dissolved in ethyl acetate and thesolution was washed with water, and then dried. After evaporation of thesolvent, the residue was purified by column chromatography on silica gelto give the title compound as colorless crystals(0.37 g, 70%). ¹H-NMRand IR spectra indicate that the product according to this workingExample is completely identical with that obtained in Working Example 4.

Reference Example 14 2-(4-Formylphenyl)benzonitrile

A mixture of 2-(4-bromomethylphenyl)benzonitrile (12 g) and sodiumbicarbonate (26 g) in dimethyl sulfoxide (150 ml) was heated at 120° C.for 5 hours with stirring. After addition of water, the mixture wasextracted with ethyl acetate. The extract was washed with water, driedand concentrated to dryness. The residue was purified by columnchromatography on silica gel to give crystals. Recrystallization fromchloroform-isopropyl ether gave colorless needles (5.77 g, 63%).

¹H-NMR(200 MHz,CDCl₃) δ: 7.49-7.58(2H,m), 7.67-7.84(4H,m),8.00-8.05(2H,m), 10.10(1H,s)

Reference Example 15 2-(4-Aminomethylphenyl)benzonitrile

A mixture of 2-(4-bromomethylphenyl)benzonitrile (12 g) and potassiumphtalimide (15 g) in DMF (200 ml) was stirred at 70° C. for 5 hours.After addition of water, the mixture was extracted with methylenechloride. The extract was washed with water, dried and concentrated todryness to give crystals. Recrystallization from ethyl acetate-isopropylether gave colorless crystals. To a suspension of the crystals inmethanol (500 ml) was added hydrazine hydrate (10 ml) and the mixturewas refluxed for 12 hours. After evaporation of the solvent, the residuewas dissolved in ethyl acetate and the solution was washed with 1N-NaOHand water. The organic layer was dried and concentrated to dryness togive crystals (14.2 g, 93%).

¹H-NMR(200 MHz,CDCl₃) δ: 1.56(2H,brs), 3.88(2H,s),7.27-7.78(8H,m)

Working Example 28 Ethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

A mixture of ethyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2ethoxybenzimidazole-7-carboxylate(0.7 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heatedunder reflux for 4 days. The reaction mixture was concentrated todryness and to the residue were added methanol (20 ml) and 1N-HCl (10ml). The mixture was stirred at room temperature for 30 minutes andadjusted to pH 3 to 4 with 1N NaOH. After removal of the solvent, theresidue was partitioned between chloroform and water. The organic layerwas washed with water and dried, and the solvent was evaporated todryness to give a syrup. The syrup was purified by column chromatographyon silica gel to give crystals. Recrystallization from ethylacetate-benzene afforded colorless crystals (0.35 g, 45%), m.p. 158-159°C.

Elemental Analysis for C₂₆H₂₄N₆O₃:

C (%) H (%) N (%) Calcd.: 66.65; 5.16; 17.94 Found: 66.61; 5.05; 17.84

¹H-NMR(200 MHz,CDCl₃) δ: 1.09(3H,t), 1.43(3H,t), 4.02(2H,q), 4.30(2H,q),5.57(2H,s), 6.71(2H,d), 6.83-6.96(4H,m), 7.27-7.31(1H,m), 7.40(1H,dd),7.55-7.66(2H,m), 8.04-8.09(1H,m)

IR(KBr) cm⁻¹: 1720, 1605, 1540, 1470, 1430, 1250, 1040, 750

Working Example 292-Ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylicacid

A solution of ethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate(0.24 g) and 1N NaOH (1.5 ml) in ethanol (4 ml) was stirred at 80° C.for one hour. The reaction mixture was concentrated, and the concentratewas extracted with water and ethyl acetate. The aqueous layer wasadjusted to pH 3-4 with 1N-HCl to give crystals. Recrystallization ofthe crystals from ethyl acetate-methanol afforded colorless crystals(0.15 g, 67%), m.p. 183-185° C.

Elemental Analysis for C₂₄H₂₀N₆O₃.1/5H₂O:

C (%) H (%) N (%) Calcd.: 64.91; 4.63; 18.93 Found: 65.04; 4.51; 18.77

¹H-NMR(200 MHz,DMSO-d₆) δ: 1.38(3H,t), 4.58(2H,q), 5.63(2H,s),6.97(4H,q), 7.17(1H,t), 7.47-7.68(6H,m)

IR(KBr) cm⁻¹: 1710, 1550, 1480, 1430, 1280, 1240, 1040, 760

Working Example 30 Ethyl2-pronoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate

A mixture of ethyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-propoxybenzimidazole-7-carboxylate(0.69 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heatedfor 4 days under reflux. The reaction mixture was concentrated todryness and to the mixture was added methanol (20 ml) and 1N-HCl (10ml). After stirring at room temperature for 30 minutes, the mixture wasadjusted to pH 3-4 with 1N NaOH. After removal of the solvent, theresidue was extracted with chloroform-water. The organic layer waswashed with water and dried, and the solvent was evaporated to drynessto give a syrup. The syrup was purified by column chromatography onsilica gel to give crystals. Recrystallization from ethylacetate-benzene afforded colorless crystals (0.31 g, 43%), m.p. 157-159°C.

Elemental Analysis for C₂₇H₂₆N₆O₃:

C (%) H (%) N (%) Calcd.: 67.21; 5.43; 17.42 Found: 67.26; 5.45; 17.28

¹H-NMR(200 MHz,CDCl₃) δ: 1.03(3H,t), 1.13(3H,t), 1.75-1.92(2H,m),4.05(2H,q), 4.23(2H,q), 5.57(2H,s), 6.75(2H,d), 6.90(2H,d), 6.96(2H,d),7.28-7.33(1H,m), 7.39-7.44(2H,m), 7.57-7.62(2H,m), 8.07-8.11 (1H,m)

IR(KBr) cm⁻¹: 1720, 1540, 1470, 1430, 1280, 1250, 1130, 1020, 750

Working Example 312-Propoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylicacid

A solution of ethyl2-propoxy-1-[[2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylate(0.23 g) in ethanol (4 ml) containing 1N-NaOH (1.5 ml) was heated at 80°C. for 2 hours. The reaction mixture was concentrated to dryness and theresidue was extracted with water and ethyl acetate. The aqueous layerwas adjusted to pH 3-4 with 1N-HCl to give crystals. Recrystallizationfrom ethyl acetate-methanol afforded colorless crystals (0.15 g, 69%),m.p. 174-175° C.

Elemental Analysis for C₂₅H₂₂N₆O₃.O.3H₂O:

C (%) H (%) N (%) Calcd.: 65.29; 4.95; 18.27 Found: 65.41; 4.92; 18.20

¹H-NMR(200 MHz,DMSO-d₆) δ: 0.92(3H,t), 1.70-1.87(2H,m), 4.47(2H,q),5.63(2H,s), 6.96(4H,dd), 7.16(1H,t), 7.42-7.67(6H,m)

IR(KBr) cm⁻¹: 1700, 1550, 1430, 1290, 1240, 765

Working Example 32 Ethyl2-mercapto-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate

A mixture of ethyl[1-(2′-cyanobiphenyl-4-yl)methyl]-2-mercaptobenzimidazole-7-carboxylate(4.1 g) and trimethyltin azide (8.0 g) in toluene (100 ml) was heatedfor 4 days under reflux. The solvent was evaporated to dryness and theresidue was stirred in a mixture of conc. hydrochloric acid (2 ml) andmethanol (20 ml) at room temperature for 20 minutes. To the reactionmixture was added 1N-NaOH to adjust to about pH 4 and then the mixturewas extracted with ethyl acetate. The organic layer was washed withwater, dried, and concentrated to dryness to give crystals.Recrystallization from chloroform gave colorless crystals (5.0 g, 89%),m.p. 263-264° C. (decomp.).

Elemental Analysis for C₂₄H₂₀N₆O₂S.1/2H₂O:

C (%) H (%) N (%) Calcd.: 61.92; 4.55; 18.05 Found: 61.99; 4.30; 17.86

¹H-NMR(200 MHz,DMSO-d₆) δ: 1.10(3H;t), 4.09(2H,q), 5.82(2H,br s),6.87(2H,d), 7.00(2H,d), 7.26(1H,t), 7.37-7.69(6H,m)

IR(KBr) cm⁻¹: 1720, 1460, 1440, 1365, 1340, 1260, 1180, 1145, 1150,1110, 990, 745

Working Example 33 Ethyl2-methylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate

To a solution of ethyl2-mercapto-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]benzimidazole-7-carboxylate(0.68 g) in ethanol (10 ml) containing 1N-NaOH (3.0 ml) was added methyliodide (0.24 g), and the mixture was stirred at room temperature for 2hours. The reaction mixture was neutralized with dilute hydrochloricacid to give crystals. The crystals were purified by columnchromatography on silica gel. Recrystallization from ethyl acetateafforded colorless prisms (0.31 g, 44%), m.p. 207-208° C. (decomp.).

Elemental Analysis for C₂₅H₂₂N₆O₂S:

C (%) H (%) N (%) Calcd.: 63.81; 4.71; 17.86 Found: 63.55; 4.81; 17.50

¹-NMR(200 MHz,DMSO-d₆) δ: 1.13(3H,t), 2.77(3H,s), 4.14(2H,q),5.62(2H,s), 6.84(2H,d), 7.26(1H,t), 7.46-7.70(5H,m)

IR(KBR) cm⁻¹: 1705, 1480, 1450, 1420, 1360, 1340, 1275, 1255, 1190,1140, 1100, 1025, 990, 770, 750

Working Example 34 Ethyl2ethylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

To a solution of ethyl2-mercapto-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate(0.91 g) in ethanol (13 ml) containing 1N-NaOH (4 ml) was added ethyliodide (0.34 g), and the mixture was stirred at room temperature for 4hours. The reaction mixture was adjusted to pH 4 with dilutehydrochloric acid to give crystals. The crystals were collected byfiltration and purified by column chromatography on silica gel.Recrystallization from ethyl acetate gave colorless prisms (0.55 g,57%), m.p. 153-154° C. (decomp.).

Elemental Analysis for C₂₆H₂₄N₆O₂S:

C (%) H (%) N (%) Calcd.: 64.44; 4.99; 17.34 Found: 64.37; 5.05; 17.20

¹H-NMR(200 MHz,,CDCl₃) δ: 1.19(3H,t), 1.37(3H,t), 3.20(2H,q),4.12(2H,q), 5.67(2H,s), 6.75(2H,d), 6.92(2H,d), 7.05(1H,t),7.26-7.34(2H,m), 7.50(1H,dd), 7.53-7.63(2,m), 8.05-8.11(1H,m)

IR(KBr) cm⁻¹: 1715, 1450, 1420, 1365, 1345, 1280, 1195, 1145, 1110,1035, 1015, 990, 760, 745

Working Example 35 Ethyl2-propylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Propyl iodide (0.37 g) was added to a solution of ethyl2-mercapto-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylate(0.91 g) in ethanol (13 ml) containing 1N NaOH (4.0 ml) and the mixturewas stirred at room temperature for 5 hours. The reaction mixture wasadjusted to about pH 4 with dilute hydrochloric acid to give crystals.The crystals were collected by filtration and purified by columnchromatography on silica gel. Recrystallization from ethylacetate-hexane gave colorless prisms (0.4 g, 40%), m.p. 177-178° C.(decomp.).

Elemental Analysis for C₂₇H₂₆N₆O₂S:

C (%) H (%) N (%) Calcd.: 65.04; 5.26; 16.85 Found: 64.88; 5.25; 16.78

¹H-NMR(200 MHz,CDCl₃) δ: 1.04(3H,t), 1.19(3H,t), 1.76(2H,m), 3.18(2H,t),4.12(2H,q), 5.69(2H,s), 6.75(2H,d), 6.93(2H,d), 7.05(1H,t),7.27-7.34(2H,m), 7.50(1H,dd), 7.54-7.63(2H,m), 8.07-8.12(1H,m)

IR(KBr) cm⁻¹: 1715, 1450, 1420, 1380, 1365, 1350, 1280, 1260, 1190,1145, 1035, 1020, 990, 760, 745

Working Example 362-Methylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylicacid

A solution of ethyl2-methylthio-1-[[2′-(1H-tetrazol-5yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate(0.2 g) in a methanol (5 ml) solution containing 1N NaOH (1.3 ml) washeated under reflux for 2 hours. The reaction mixture was adjusted toabout pH 4 with dilute hydrochloric acid to give crystals. The crystalswere collected by filtration, and recrystallized from ethylacetate-hexane to give colorless crystals (0.17 g, 81%), m.p. 223-225°C. (decomp.).

Elemental Analysis for C₂₃H₁₈N₆O₂S.1/2C₄H₈O₂

C (%) H (%) N (%) Calcd.: 61.72; 4.56; 17.27 Found: 61.59; 4.54; 17.54

¹H-NMR(200 MHz,DMSO-d₆) δ: 2.75(3H,s), 5.76(2H,r.), 6.88(2H,d),7.01(2H,d), 7.25(1H,t), 7.47-7.66(5H,m), 7.82(1H,d)

IR(KBR) cm⁻¹: 1710, 1485, 1450, 1420, 1370, 1345, 1320, 1280, 1245,1195, 1150, 990, 780, 760

Working Example 372-Ethylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylicacid

A solution of ethyl2-ethylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate(0.35 g) in a methanol (7 ml) solution containing 1N NaOH (2.2 ml) washeated under reflex for 2 hours. After evaporation of the solvent, theaqueous residue was adjusted to about pH 3-4 with 1N-HCl to givecrystals. The crystals were collected by filtration. Recrystallizationfrom ethyl acetate-methanol gave colorless crystals (0.21 g, 64%), m.p.209-210° C. (decomp.).

Elemental Analysis for C₂₄H₂₀N₆O₂S:

C (%) H (%) N (%) Calcd.: 63.14; 4.42; 18.41 Found: 62.89; 4.35; 18.15

¹H-NMR(200 MHz,DMSO-d₆) δ: 1.39(3H,t), 3.36(2H,q), 5.76(2H,s),6.87(2H,d), 7.01(2H,d), 7.25(1H,t), 7.47-7.69(5H,m), 7.82(1H,dd)

IR(KBr) cm⁻¹: 1695, 1450, 1415, 1350, 1275, 1225, 1190, 1180, 1145, 755,740

Working Example 382-Propylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylicacid

A solution of ethyl2-propylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate(0.25 g) in methanol (5 ml) containing 1N-NaOH (1.5 ml) was heated underreflux for 2 hours. After removal of the solvent, the aqueous residuewas adjusted to about pH 3-4 with 1N-HCl to give crystals. The crystalswere collected by filtration. Recrystallization from ethylacetate-hexane gave colorless crystals (0.21 g, 91%), m.p. 222-223° C.(decomp.).

Elemental Analysis for C₂₅H₂₁N₆O₂S:

C (%) H (%) N (%) Calcd.: 63.95; 4.51; 17.90 Found: 63.78; 4.85; 17.59

¹H-NMR(200 MHz,DMSO-d₆) δ: 0.99(3H,t), 1.67-1.85(2H,m), 3.35(2H,t),5.77(2H,s), 6.87(2H,d), 7.01(2H,d), 7.25(1H,t), 7.46-7.70(5H,m),7.82(1H,dd)

IR(KBr) cm⁻¹: 1700, 1450, 1280, 1240, 1195, 1145, 755, 740

Working Example 39 Methyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

A mixture of methyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate(1.85 g) and trimethyltin azide (2.80 g) in toluene (15 ml) were heatedunder reflux for one day. The reaction mixture was concentrated todryness. To the residue were added methanol (50 ml) and 1N-HCl (20 ml)and the mixture was stirred at room temperature for 30 minutes. Thereaction mixture was adjusted to about pH 3-4 with 1N-NaOH. Afterremoval of the solvent, the residual syrup was purified by columnchromatography on silica gel to give crystals. Recrystallization fromethyl acetate-benzene gave colorless crystals (1.16 g, 56%), m.p.191-193° C. (decomp.).

Elemental Analysis for C₂₅H₂₂N₆O₃.1/5H₂O:

C (%) H (%) N (%) Calcd.: 65.58; 4.75; 18.53 Found: 65.55; 4.93; 18.35

¹H-NMR(200 MHz,CDCl₃) δ: 1.43(3H,t,J=7.0 Hz)), 3.57(3H,s),4.30(2H,q,J=7.00 Hz), 5.54(2H,s), 6.72(2H,d,J=8.2), 6.84-6.97(4H,m),7.28-7.33(1H,m), 7.40(1H,dd,J=1.8,7.0 Hz), 7.57-7.62(2H,m),8.03-8.07(1H,m)

IR(KBr) cm⁻¹: 1720, 1550, 1475, 1430, 1280, 1250, 1040, 755, 735

Working Example 40 Ethyl2-ethylamino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-carboxylate

A mixture of ethyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethylaminobenzimidazole-7-carboxylate(1.23 g) and trimethyltin azide (2.80 g) in toluene (15 ml) was heatedfor 40 hours under reflux. Precipitates were collected by filtration andsuspended in methanol (50 ml). To the suspension was added 1N-HCl (15ml), and the mixture was stirred at room temperature for 10 minutes. Thereaction mixture was adjusted to about pH 5 with 1N-NaOH, followed byextraction with chloroform. The organic layer was washed with water,dried and concentrated to dryness. The residue was purified by columnchromatography on silica gel to give crystals. Recrystallization frommethanol-ethyl acetate gave colorless crystals (0.83 g, 61%), m.p.166-168° C.

¹H-NMR(200 MHz,CDCl₃) δ: 1.13(3H,t), 1.21(3H,t), 343(2H,q), 4.13(2H,q),5.48(2H,s), 6.78(2H,d), 6.99(2H,d), 7.07(1H,t), 7.22(1H,dd),7.42-7.49(2H,m), 7.54-7.69(3H,m)

IR(KBr) cm⁻¹: 1720, 1650, 1310, 1285, 765, 755, 750

Working Example 41 Ethyl2-propylamino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

A solution of ethyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-propylaminobenzimidazole-7-carboxylate(1.20 g) and trimethyltin azide (2.7 g) in toluene (15 ml) was heatedfor 50 hours under reflux. Precipitates were collected by filtration andsuspended in methanol (20 ml). After addition of 1N-HCl (15 ml), thereaction mixture was stirred at room temperature for 10 minutes. Themixture was adjusted to about pH 5 with 1N-NaOH, followed by extractionwith chloroform. The organic layer was washed with water, dried andconcentrated to dryness. The concentrate was purified by columnchromatography on silica gel to give crystals. Recrystallization frommethanol-ethyl acetate gave colorless crystals (10 g, 77%), m.p.170-172° C.

¹H-NMR(200 MHz,CDCl₃) δ: 0.89(3H,t), 1.14(3H,t), 1.52-1.70(2H,m),3.35(2H,t), 4.14(2H,q), 5.49(2H,s), 6.77(2H,d), 6.99(2H,d), 7.05(1H,t),7.21(1H,dd), 7.39-7.47(2H,m), 7.50-7.65(3H,m)

IR(KBr) cm⁻¹: 1720, 1670, 1660, 1290, 1270, 760

Working Example 422-Ethoxy-1-[[2′-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid

To a solution of2-ethoxy-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid (2.07 g) in methylene chloride (10 ml) were added trityl chloride(1.59 g) and triethylamine (0.8 ml). The mixture was stirred at roomtemperature for one hour. The reaction mixture was washed with water,dried and concentrated to dryness. The residue was purified by columnchromatography on silica gel to give crystals. Recrystallization ofcrude crystals thus obtained from ethyl acetate-benzene gave colorlesscrystals (2.12 g, 66%), m.p. 168-170° C.

Elemental Analysis for C₄₃H₃₄N₆O₃:

C (%) H (%) N (%) Calcd.: 75.64; 5.02; 12.31 Found: 75.37; 4.96; 12.20

¹H-NMR(200 MHz,CDCl₃) δ: 1.40(3H,t), 4.61(2H,q), 5.58(2H,s), 6.76(2H,d),6.91-6.96(8H,m), 7.12(1H,t), 7.17-7.41(12H,m), 7.60(1H,dd),7.73-7.82(2H,m)

Working Example 43 Pivaloyloxymethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]benzimidazole-7-carboxylate

To a solution of2-ethoxy-1-[[2′-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid (2.2 g) in DMF (10 ml) were added potassium carbonate (0.53 g) andpivaloyloxymethyl iodide (0.94 g), and the mixture was stirred for 30minutes at room temperature. To the reaction mixture was added water andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and dried. After removal of the solvent, the residuewas dissolved in methanol (30 ml) and 1N-HCl (6 ml). The mixture wasstirred for one hour at room temperature. The reaction mixture wasconcentrated to dryness and the residue was partitioned between waterand ethyl acetate. The organic layer was washed with water and dried.After removal of the solvent, the residue was purified by columnchromatography on silica gel to give crystals. The crystals wererecrystallized from ethyl acetate-hexane to give colorless crystals(1.13 g, 63%), m.p. 104-106° C.

Elemental Analysis for C₃₀H₃₀N₆O₅.1/5C₄H₈O₂.1/5C₆H₁₄:

C (%) H (%) N (%) Calcd.: 65.06; 5.90; 14.32 Found: 64.79; 5.85; 14.43

¹H-NMR(200 MHz,CDCl₃) δ: 1.13(9H,s), 1.44(3H,t), 4.37(2H,q), 5.61(2H,s),5.68(2H,s), 6.80(2H,d), 6.93(2H,d), 6.99-7.11(2H,m), 7.33-7.37(1H,m),7.49-7.54(1H,m), 7.59-7.62(2H,m), 8.03-8.07(1H,m)

Working Example 44 1-(Cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

To a solution of2-ethoxy-1-[[2′-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid (0.5 g) in DMF (5 ml) were added potassium carbonate (0.12 g) andcyclohexyl 1-iodoethyl carbonate (0.26 g). The mixture was stirred forone hour at room temperature. To the reaction mixture was added waterand the mixture was extracted with ethyl acetate. The organic layer waswashed with water and dried. After removal of the solvent, the residuewas dissolved in methanol (10 ml) and to the solution was added 1N-HCl(2 ml). The mixture was stirred for one hour at room temperature. Thereaction mixture was concentrated to dryness and the residue waspartitioned between ethyl acetate and water. The organic layer waswashed with water and dried. After removal of the solvent, the residuewas purified by column chromatography on silica gel to give colorlesspowder (0.21 g, 47%), m.p. 103-106° C.

Elemental Analysis for C₃₃N₃₄N₆O₆:

C (%) H (%) N (%) Calcd.: 64.91; 5.61; 13.76 Found: 64.94; 5.71; 13.66

To the powder (1 g) obtained as above was added ethanol (6 ml). Themixture was stirred for 3 hours at room temperature and allowed to standunder ice-cooling. The mixture was then stirred for one hour attemperatures not higher than 10° C. Resultant crystals were collected byfiltration and washed with cold ethanol. The crystals were dried at 25°C. for 9 hours under reduced pressure, then at 35° C. for further 18hours to obtain white powdery crystals (0.94 g), m.p. 158-166° C.(decomp.).

Elemental Analysis for C₃₂H₃₄N₆O₆:

C (%) H (%) N (%) Calcd.: 64.91; 5.61; 13.76 Found: 64.73; 5.66; 13.64

¹H-NMR (200 MHz) δ: 1.13-1.84(16H,m), 4.28-4.55(3H,m), 5.65(2H,d),6.72(1H,q), 6.81(2H,d), 6.93(2H,d), 7.03(1H,t), 7.22-7.23(1H,m),7.31-7.36(1H,m), 7.52-7.60(3H,m), 8.02-8.07(1H,m)

IR(KBR) cm⁻¹: 2942, 1754, 1717, 1549, 1476, 1431, 1076, 1034, 750

MS(m/z) : 611 [M+H]⁺

Working Example 45 Methyl2-methoxy-1-[[2′-(1H-tetrazol-5-yl-4-yl]methyl]benzimidazole-7-carboxylate

Methyl[1-(2′-cyanobiphenyl-4-yl)methyl]-2-methoxybenzimidazole-7-carboxylate(0.60 g) and trimethyltin azide (1.5 g) in toluene (15 ml) were heatedfor 40 hours under reflux. Precipitated crystals were dissolved inmethanol (10 ml) and to the solution was added 1N-HCL (3 ml). Themixture was stirred for 10 minutes at room temperature and the methanolwas evaporated. The aqueous residue was adjusted to pH 3-4 with 1N-NaOH,followed by extraction with ethyl acetate. The organic layer was washedwith water and dried. After removal of the solvent, the residue waspurified by column chromatography on silica gel to give crystals. Thecrystals were recrystallized from ethyl acetate to give colorless prisms(0.65 g, 65%), m.p. 165-166° C.

Elemental Analysis for C₂₄H₂₀N₆O₃.1/10H₂O:

C (%) H (%) N (%) Calcd.: 65.18; 4.60; 19.00 Found: 64.91; 4.49; 18.99

¹H-NMR(200 MHz,CDCl₃) δ: 3.64(3H,s), 3.93(3H,s), 5.55(2H,s), 6.75(2H,d),6.90-7.01(4H,m), 7.31-7.36(1H,m), 7.49(1H,dd), 7.55-7.64(2H,m),8.03-8.07(1H,m)

Working Example 462-Methoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylicacid

To a solution of methyl2-methoxy-1-[[2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylate(0.22 g) in methanol (10 ml) was added 1N-NaOH (1.5 ml). The mixture washeated for 6 hours under reflux. The reaction mixture was concentratedto dryness and to the residue was added water. The mixture was adjustedto pH 3-4 with 1N-HCl to give crystals. Recrystallization frommethanol-chloroform gave colorless needles (0.17 g, 77%), m.p. 208-209°C.

Elemental Analysis for C₂₃H₁₈N₆O₃.O.7H₂O:

C (%) H (%) N (%) Calcd.: 62.92; 4.45; 19.14 Found: 62.81; 4.08; 19.19

¹H-NMR(200 MHZ,DMSO-d₆) δ: 4.15(3H,s), 5.63(2H,s), 6.90(2H,d),7.00(2H,d), 7.18(1H,t), 7.46-7.70(6H,m)

Working Example 47 2-Ethylamino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylicacid

To a solution of ethyl2-ethylamino-1-[[2′-(1H-tetrazol-5yl)biphenyl-4-yl]benzimidazole-7-carboxylate(0.52 g) in ethanol (5 ml) was added 1N-NaOH (4 ml), and the mixture wasstirred for 2 hours at 80° C. The reaction mixture was concentrated todryness and the aqueous residue was adjusted to pH 4-5 with 1N-HCl togive crystals. The crystals were collected by filtration andrecrystallized from methanol-chloroform to give colorless crystals (0.3g, 63.4%), m.p. 240-242° C.

Elemental Analysis for C₂₄H₂₁N₇O₂.1.1H₂O:

C (%) H (%) N (%) Calcd.: 62.76; 5.09; 21.35 Found: 62.65; 5.15; 21.23

¹H-NMR(200 MHz,DMSO-d₆) δ: 1.20(3H,t), 3.43(2H,q), 5.62(2H,s),6.85(2H,d), 6.99(2H,d), 7.10(1H,t), 7.34(1H,d), 7.44-7.68(5H,m)

Working Example 482-Propylamino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid

In substantially the same manner as Working Example 47, the abovecompound was obtained in a yield of 73%, m.p. 244-246° C.

Elemental Analysis for C₂₅H₂₃N₇O₂.1/2H₂O:

C (%) H (%) N (%) Calcd.: 64.92; 5.23; 21.20 Found: 64.79; 5.27; 21.08

In substantially the same manner as Working Example 43, the followingcompounds (Working Examples 49-53) were synthesized.

Working Example 49 (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 55%, m.p.: 122-125° C. (decomp.)

Elemental Analysis for C₂₂H₂₄N₆O₆.CHCl₃:

C (%) H (%) N (%) Calcd.: 53.63; 3.75; 12.51 Found: 53.32; 3.58; 12.24

¹H-NMR(200 MHz,CDCl₃) δ: 1.43(3H,t), 2.11(3H,s), 4.40(2H,q), 4.80(2H,s),5.58(2H,s), 6.79(2H,d), 6.94(2H,d), 7.02(1H,t), 7.15(1H,dd),7.35-7.39(1H,m), 7.49-7.63(3H,m), 8.00-8.04(1H,m)

Working Example 50 Acetoxymethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 38%, m.p.: 152-154° C. (decomp.)

Elemental Analysis for C₂₇H₂₄N₆O₅:

C (%) H (%) N (%) Calcd.: 63.27; 4.72; 16.40 Found: 63.55; 4.70; 16.18

¹H-NMR(200 MHz,CDCl₃) δ: 1.43(3H,t), 2.01(3H,s), 4.33(2H,q), 5.61(2H,s),5.69(2H,s), 6.81(2H,d), 6.93(2H,d), 7.01(tH,t), 7.13(1H,d),7.33-7.38(1H,m), 7.53-7.62(3H,m), 8.03-8.07(1H,m)

Working Example 51 Propionyloxymethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 60%, m.p.: 145-150° C. (decomp.)

Elemental Analysis for C₂₈H₂₆N₆O₅.O.2C₇H₈:

C (%) H (%) N (%) Calcd.: 64.79; 5.10; 15.42 Found: 64.70; 5.10; 15.44

¹H-NMR(200 MHz,CDCl₃) δ: 1.04(3H,t), 1.44(3H,t), 2.29(2H,q), 4.40(2H,q),5.61(2H,s), 5.71(2H,s), 6.82(2H,d), 6.92-7.14(3H,m), 7.20(1H,m),7.33-7.38(1H,m), 7.53-7.61(3H,m), 8.03-8.08(1H,m)

Working Example 52 Butyryloxymethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 36%, m.p.: 96-100° C.

Elemental Analysis for C₂₈H₂₈N₆O₅.O.4C₇H₈:

C (%) H (%) N (%) Calcd.: 66.15; 5.45; 14.55 Found: 66.11; 5.44; 14.65

¹H-NMR(200 MHz,CDCl₃) δ: 0.85(3H,t), 1.44(3H,t), 1.55(2H,m), 2.24(2H,q),4.38(2H,q), 5.61(2H,s), 5.70(2H,s), 6.81(2H,d), 6.93(2H,d), 7.00(1H,t),7.20(1H,m), 7.33-7.38(1H,m), 7.52-7.61(3H,m), 8.01-8.10(1H,m)

Working Example 53 Isobutyryloxymethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 53%, m.p.: 143-145° C.

Elemental Analysis for C₂₈H₂₈N₆O₅.O.1C₇H₈:

C (%) H (%) N (%) Calcd.: 64.88; 5.28; 15.29 Found: 65.04; 5.25; 15.18

¹H-NMR(200 MHz, CDCl₃) δ: 1.09(6H,d), 1.44(3H,t), 2.50(1H,m),4.38(2H,q), 5.61(2H,s), 5.70(2H,s), 6.81(2H,d), 6.91-7.00(3H,m),7.19(1H,m), 7.33-7.37(1H,m), 7.51-7.63(3H,m), 8.02-8.07(1H,m)

In substantially the same manner as Working Example 44, the followingcompounds (Working Examples 54-56) were synthesized.

Working Example 54 1-(Ethoxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 44%, m.p.: 85-87° C.

Elemental Analysis for C₂₉H₂₈N₆O₆.O.3H₂):

C (%) H (%) N (%) Calcd.: 61.98; 5.13; 14.95 Found: 62.11; 5.02; 14.69

¹H-NMR(200 MHz,CDCl₃) δ: 1.20(3H,t), 1.30(3H,d), 1.41(3H,t),4.03-4.22(3H,m), 4.31-4.47(1H,m), 5.61(2H,s), 6.62-6.72(3H,m),6.80-6.95(4H,m), 7.29-7.32(1H,m), 7.47(1H,dd), 7.54-7.64(2H,m),7.97-8.01 (1H,m)

Working Example 55 1-Acetoxyethyl2-ethoxy-1-[[2′-1-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 31%, m.p.: 105-107° C.

Elemental Analysis for C₂₈H₂₆N₆O₅.O5H₂O:

C (%) H (%) N (%) Calcd.: 62.80; 5.08; 15.69 Found: 62.77; 4.69; 15.85

¹H-NMR(200 MHz,CDCl₃) δ: 1.46(3H,t), 1.49(3H,d), 4.47-4.62 (2H,m),5.59(1H,d), 5.83(1H,d), 6.84(1H,q), 6.90(2H,d), 7.03(2H,d), 7.11(1H,t),7.34-7.39(1H,m), 7.49(1H,d), 7.53-7.61(3H,m), 8.07-8.11(1H,m)

Working Example 56 1-(Isopropoxycarbonylcxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 33%, m.p.: 74-76° C.

Elemental Analysis for C₃₀H₃₀N₆O₅.1.5H₂O:

C (%) H (%) N (%) Calcd.: 61.95; 5.72; 14.45 Found: 62.02; 5.43; 14.20

¹H-NMR(200 MHz,CDCl₃) δ: 1.20(3H,d), 1.21(3H,d), 1.30(3H,d), 1.42(3H,t),4.08-4.24(1H,m), 4.34-4.50(1H,m), 4.79(1H,m), 5.61(2H,s),6.62-6.75(3H,m), 7.27-7.32(1H,m), 7.48(1H,dd), 7.54-7.64(2H,m),7.98-8.03(1H,m)

Working Example 572-Methylamino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylicacid

The above compound was synthesized by substantially the same manner asWorking Examples 40 and 47.

Yield: 40%, m.p.: 247-250° C. (decomp.)

Elemental Analysis for C₂₃H₁₉N₇O₂.2.OH₂O:

C (%) H (%) N (%) Calcd.: 59.86; 5.02; 21.25 Found: 59.99; 4.89; 21.36

¹H-NMR(200 MHz,CDCl₃) δ: 2.94(3H,s), 5.64(2H,s), 6.82(2H,d), 6.99(2H,d),7.02(1H,t), 7.31(1H,d), 7.42-7.63(5H,m)

In substantially the same manner as Working Example 43, the followingcompounds (Working Examples 58-60) were synthesized.

Working Example 58 Cyclohexylcarbonyloxymethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 54%, m.p.: 140-142° C.

Elemental Analysis for C₃₂H₃₂N₆O₅:

C (%) H (%) N (%) Calcd.: 66.19; 5.55; 14.47 Found: 65.93; 5.46; 14.39

¹H-NMR(200 MHz,CDCl₃) δ: 1.21-1.87(13H,m), 2.20-2.32(1H,m), 4.47(2H,q),5.60(2H,s), 5.73(2H,s), 6.86(2H,d), 7.07(1H,t), 7.27-7.40(3H,m),7.54-7.61(2H,m), 8.05-8.09(1H,m)

Working Example 59 Benzoyloxymethyl2-ethoxy-1-[[2′-1H-tetrazol-5-yl)biphenyl-4yl]methyl]benzimidazole-7-carboxylate

Yield: 47%, m.p.: 138-142° C.

Elemental Analysis for C₃₂H₂₆N₆O₅.O.5H₂O.O.1C₄H₈O₂:

C (%) H (%) N (%) Calcd.: 65.67; 4.76; 14.18 Found: 65.71; 4.66; 13.96

¹H-NMR(200 MHz,CDCl₃) δ: 1.43(3H,t), 4.36(2H,q), 5.60(2H,s), 5.98(2H,s),6.74(4H,s), 6.99(1H,t), 7.09-7.14(1H,m), 7.21-7.36(3H,m),7.50-7.59(4H,m), 7.90(2H,d), 8.02-8.06(1H,m)

Working Example 60 (E)-cinnamoyloxymethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 56%, m.p.: 146-147° C.

Elemental Analysis for C₃₄H₂₈N₆O₅.O.4C₈H₈O₂:

C (%) H (%) N (%) Calcd.: 67.16; 5.07; 13.20 Found: 66.97; 4.86; 13.28

¹H-NMR(200 MHz,CDCl₃) δ: 1.44(3H,t), 4.45(2H,q), 5.61(2H,s), 5.87(2H,s),6.33(1H,d), 6.84(2H,d), 6.96(2H,d), 7.05(1H,t) 7.31-7.57(10H,m),7.65(1H,d), 8.00-8.04(1H,m)

In substantially the same manner as Working Examples 43 and 44, thefollowing compounds (Working Examples 61-63) were synthesized.

Working Example 61 Cyclopentylcarbonyloxymethyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 54%, m.p.: 136-138° C.

Elemental Analysis for C₃₁H₃₀N₆O₅:

C (%) H (%) N (%) Calcd.: 65.71; 5.34; 14.83 Found: 65.59; 5.33; 14.67

¹H-NMR(200 MHz,CDCl₃) δ: 1.41-1.84(11H,m), 2.61-2.76(1H,m), 4.43(2H,q),5.61(2H,s), 5.72(2H,s), 6.84(2H,d), 6.96(2H,d), 7.05(1H,t),7.22-7.26(1H,m), 7.35-7.39(1H,m), 7.53-7.61(3H,m), 8.03-8.08(1H,m)

Working Example 62 Pivaloyloxymethyl2-ethylamino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 59%, m.p.: 130-135° C.

Elemental Analysis for C₃₀H₃₁N₇O₄.O.4CHCl₃.O2H₂O:

C (%) H (%) N (%) Calcd.: 60.36; 5.30; 16.21 Found: 60.20; 5.20; 16.08

¹-NMR(200 MHz,CDCl₃) δ: 1.12(9H,s), 1.20(3H,t), 3.43(2H,q), 5.52(2H,s),5.81(2H,s), 6.80(2H,d), 6.99(2H,d), 7.08(1H,t), 7.24(1H,dd),7.43-7.68(5H,m)

Working Example 63 1-(Cyclohexyloxycarbonyloxy)ethyl2-ethylamino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

Yield: 76%, m.p.: 149-152° C.

Elemental Analysis for C₃₃H₃₅N₇O₅.O.5H₂O:

C (%) H (%) N (%) Calcd.: 64.06; 5.86; 15.85 Found: 64.27; 6.02; 15.86

¹H-NMR(200 MHz,CDCl₃) δ: 1.12-1.88(16H,m), 3.38-3.47(2H,m),4.48-4.59(1H,m), 5.51(2H,s), 6.75-6.88(5H,m), 7.04(1H,t),7.29-7.40(2H,m), 7.47-7.51(3H,m), 7.91-7.95(1H,m)

Working Example 64 Methyl2-allyloxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate

The title compound was prepared as colorless crystals from methyl2-allyloxy-1- [[2′-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylateaccording to the procedure for Working Example 28.

Yield: 30%, m.p.: 154-156° C.

Elemental Analysis for C₂₆H₂₂N₆O₃.O.5H₂O:

C (%) H (%) N (%) Calcd.: 65.67; 4.88; 17.67 Found: 65.63; 4.71; 17.68

¹H-NMR(200 MHz,CDCl₃) δ: 3.75(3H,d), 4.58-4.61(1H,m), 4.92-4.95(1H,m),5.18-5.48(2H,m), 5.52(2H,d), 5.83-6.15(1H,m), 6.98-7.05(2H,m),7.09-7.17(2H,m), 7.35-7.44(2H,m), 7.47-7.60(3H,m), 8.09-8.19(1H,m)

IR(KBr) cm⁻¹: 1720, 1670, 1550, 1470, 1430, 1260, 1250, 1025, 760, 735

Working Example 65 Methyl2-butoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate

The title compound was prepared as colorless needles from methyl2-butoxy-1-[(2′-cyanobiphenyl-4-yl]methyl]benzimidazole-7-carboxylateaccording to the procedure for Working Example 28.

Yield: 91%, m.p.: 146-148° C.

Elemental Analysis for C₂₇H₂₆N₆O₃O:

C (%) H (%) N (%) Calcd.: 67.21; 5.43; 17.42 Found: 67.00; 5.45; 17.49

¹H-NMR(200 HHz,CDCl₃) δ: 0.99(3H,t), 1.37-1.55(2H,m), 1.74-1.88(2H,m),3.61(3H,s), 4.27(2H,t), 5.53(2H,s), 6.75(2H,d), 6.90(2H,d), 6.97(2H,d),7.30-7.34(1H,m), 7.41(2H,dd), 7.57-7.61(2H,m), 8.04-8.09(1H,m)

IR(KBr) cm⁻¹: 1720, 1600, 1540, 1470, 1430, 1270, 1250, 1020, 750

Working Example 66 Methyl2-butylamino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate

The title compound was prepared as colorless crystals from methyl2-butylamino-1-[(2′-cyanobiphenyl-4-yl]methyl]benzimidazole-7-carboxylateaccording to the procedure for Working Example 41.

Yield: 42%, m.p.: 216-218° C.

Elemental Analysis for C₂₇H₂₇N₇O₂.H₂O:

C (%) H (%) N (%) Calcd.: 64.91; 5.85; 19.63 Found: 64.86; 5.68; 19.41

¹H-NMR (200 MHz, DMSO-d₆) δ: 0.91(3H,t), 1.25-1.43(2H,m),1.52-1.67(2H,m), 3.65(3H,s), 5.47(2H,s), 6.79(2H,d), 6.98-7.05(3H,m),7.18(1H,dd), 7.42-7.64(5H,m)

IR(KBr) cm⁻¹: 1720, 1665, 1660, 1650, 1430, 1260, 745

Working Example 67 Methyl1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-2morpholinobenzimidazole-7-carboxylate

The title compound was prepared as colorless crystals from methyl1-[(2′-cyanobiphenyl-4-yl)methyl]-2-morpholinobenzimidazole-7-carboxylateaccording to the procedure for Working Example 41.

Yield: 62%, m.p.: 163-167° C.

Elemental Analysis for C₂₇H₂₅N₇O₃.O6CHCl₃:

C (%) H (%) N (%) Calcd.: 58.45; 4.55; 17.29 Found: 58.66; 4.36; 17.54

¹H-NMR(200 MHz,CDCl₃) δ: 3.33(4H,t), 3.73(3H,s), 3.90(4H,t), 5.44(2H,s),6.62(2H,d), 6.97(2H,d), 7.17(1H,t), 7.33-7.38(1H,m), 7.43-7.50(2H,m),7.55-7.61(2H,m), 8.08-8.13(1H,m)

IR(KBr) cm⁻¹: 1730, 1600, 1530, 1455, 1420, 1405, 1280, 1260, 1120,1110, 1000, 760, 750, 740

Working Example 68 Methyl1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl)]methyl]-2-piperidinobenzimidazole-7-carboxylate

The title compound was prepared as colorless crystals from methyl1-[[2′-cyanobiphenyl-4-yl)methyl]-2-piperidinobenzimidazole-7carboxylateaccording to the procedure for Working Example 41.

Yield: 47%, m.p.: 146-150° C.

Elemental Analysis for C₂₃H₂₇N₇O₂.O.8CHCl₃:

C (%) H (%) N (%) Calcd.: 58.72; 4.76; 16.64 Found: 58.69; 4.66; 16.75

¹H-NMR(200 MHz,CDCl₃) δ: 1.72(6H,brs), 3.11(4H,m), 3.61(3H,s),5.38(2H,s), 6.45(2H,d), 6.80(2H,d), 6.89-6.96(2H,m), 7.28-7.37(2H,m),7.56-7.64(2H,m), 8.01-8.06(1H,m)

IR(KBr) cm⁻¹: 1715, 1600, 1530, 1450, 1420, 1415, 1405, 1300, 1280,1260, 1240, 1215, 1130, 770, 760, 750

Working Example 69 Methyl2-ethylmethylamino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate

The title compound was prepared as colorless crystals from methyl2-ethylmethylamino-1-[(2′-cyanobiphenyl-4-yl]-methyl]benzimidazole-7-carboxylateaccording to the procedure for Working Example 41.

Yield: 54%, m.p.: 130-136° C. (decomp.).

Elemental Analysis for C₂₈H₂₅N₇O₂.O.6H₂O:

C (%) H (%) N (%) Calcd.: 59.26; 4.79; 18.19 Found: 59.04; 4.95; 18.05

¹H-NMR(200 MHz,CDCl₃) δ: 1.19(3H,t), 2.57(3H,s), 3.22(2H,m), 3.62(3H,s),5.40(2H,s), 6.43(2H,d), 6.78-6.94(4H,m), 7.30-7.34(1H,m), 7.57(1H,dd),7.59-7.63(2H,m), 7.99-8.04(1H,m)

IR(KBr) cm⁻¹: 1720, 1600, 1540, 1435, 1400, 1300, 1280, 1255, 1015, 750,740

Working Example 702-Piperidino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid

The title compound was prepared as colorless crystals from methyl1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-2-piperidinobenzimidazole-7-carboxylateaccording to the procedure for Working Example 29.

Yield: 91%, m.p.: 215-218° C. (decomp.).

Elemental Analysis for C₂₇H₂₅N₇O₂.O5CHCl₃:

C (%) H (%) N (%) Calcd.: 61.25; 4.77; 18.18 Found: 60.95; 4.70; 17.90

¹H-NMR(200 MHz,DMSO-d₆) δ: 1.65(6H,brs), 3.24(4H,brs), 5.48(2H,s),6.71(2H,d), 6.92(2H,d), 7.17(1H,t), 7.42-7.48(2H,m), 7.54-7.67(2H,m)

IR(KBr) cm⁻¹: 1685, 1530, 1450, 1440, 1420, 1400, 1285, 1270, 1245, 750,730

Working Example 712-Morpholino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid

The title compound was prepared as colorless crystals from methyl2-morpholino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylateaccording to the procedure for Working Example 29.

Yield: 59%, m.p.: 202-206° C. (decomp.).

Elemental Analysis for C₂₆H₂₃N₇O₃.O.6CHCl₃:

C (%) H (%) N (%) Calcd.: 57.76; 4.30; 17.73 Found: 57.55; 4.25; 17.66

¹H-NMR(200 MHz,DMSO-d₆) δ: 3.24(4H,brs), 3.76(4H,brs), 5.56(2H,s),6.72(2H,d), 6.93(2H,d), 7.16(1H,t), 7.41-7.70(6H,m)

IR(KBr) cm⁻¹: 1690, 1535, 1460, 1450, 1420, 1410, 1290, 1260, 1245,1120, 760, 740

Working Example 722-(N-Ethylmethylamino)-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid

The title compound was prepared as colorless crystals from methyl2-(N-ethylmethylamino)-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylateaccording to the procedure for Working Example 47.

Yield: 66%, m.p.: 204-206° C. (decomp.).

Elemental Analysis for C₂₅H₂₃N₇O₂.O5H₂O:

C (%) H (%) N (%) Calcd.: 64.92; 5.23; 21.20 Found: 65.22; 5.31; 21.11

¹H-NMR(200 MHz,CDCl₃) δ: 1.13(3H,t), 2.93(3H,s), 3.27(2H,m), 5.54(2H,s),6.68(2H,d), 6.92(2H,d), 7.13(1H,t), 7.43-7.48(2H,m), 7.53-7.67(2H,m)

IR(KBr) cm⁻¹: 1725, 1620, 1550, 1540, 1460, 1440, 1420, 1300, 1250, 775

Working Example 732-Butylamino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylicacid

The title compound was prepared as colorless crystals from methyl2-butylamino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylateaccording to the procedure for Working Example 47.

Yield: 67%, m.p.: 213-216° C. (decomp.).

Elemental Analysis for C₂₅H₂₅N₇O₂.H₂O:

C (%) H (%) N (%) Calcd.: 64.32; 5.60; 20.19 Found: 64.07; 5.77; 20.16

¹H-NMR(200 MHz,DMSO-d₆) δ: 0.89(3H,t), 1.22-1.41(2H,m), 1.51-1.66(2H,m),3.34-3.43(2H,m), 5.65(2H,s), 6.83(2H,d), 6.97-7.05(3H,m), 7.29(1H,dd),7.40-7.67(5H,m)

IR(KBr) cm⁻¹: 1660, 1580, 1540, 1485, 1440, 1380, 1340, 1215, 850, 810,780, 760, 750

Working Example 742-Ethoxy-1-[[2′-carboxybiphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid

To a solution of methyl2-ethoxy-1-[[2′-methoxycarbonylbiphenyl-4-yl]methyl]benzimidazole-7-carboxylate(0.7 g) in methanol (10 ml) was added 1N NaOH (5 ml) and the mixture wasstirred at 80° C. for 3 hours. After evaporation of the methanol, theaqueous residue was neutralized with 1N hydrochloric acid to givecrystals. The crystals were recrystallized from methanol-chloroform toafford colorless crystals (0.54 g, 83%), m.p. 213-215° C.

Elemental Analysis for C₂₄H₂₀N₂O₅:

C (%) H (%) N (%) Calcd.: 69.22; 4.84; 6.73 Found: 68.98; 4.89; 6.71

¹H-NMR(200 MHz,DMSO-d₆) δ: 1.42(3H,t), 4.61(2H,q), 5.68(2H,s),7.01(2H,d), 7.13-7.56(7H,m), 7.64-7.71(2H,m)

IR(Neat)cm⁻¹: 1725, 1545, 1460, 1420, 1380, 7280, 1260, 1230, 1205,1120, 1030, 750

Working Example 75 Methyl2-ethylamino-1-[[2′-(1H-tetrazol-5-yl)binhenyl-4-yl]methyl]benzimidazole-7-carboxylate

The title compound was prepared as colorless crystals from methyl2-ethylamino-1-[[2′-cyanobiphenyl-4-yl]methyl]benzimidazole-7carboxylateaccording to the procedure for Working Example 41.

Yield: 63%, m.p.: 256-258° C.

Elemental Analysis for C₂₅H₂₃N₇O₂H₂O:

C (%) H (%) N (%) Calcd.: 63.68; 5.34; 20.79 Found: 63.99; 5.09; 20.68

¹H-NMR(200 MHz,DMSO-d₆) δ: 1.21(3H,t), 3.40-3.60(2H,m), 3.63(3H,s),5.47(2H,s), 6.78(2H,d), 6.98-7.05(3H,m), 7.18(1H,dd), 7.42-7.66(5H,m)

IR(Neat)cm⁻¹: 1710, 1660, 1650, 1645, 1430, 1340, 1300, 1280, 1250,1050, 740

Working Example 76 Methyl1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-2-(2,2,2-trifluoroethoxy)benzimidazole-7-carboxylate

The title compound was prepared as colorless needles (0.37 g, 77%) frommethyl1-[[2′-cyanobiphenyl-4-yl]methyl]-2-(2,2,2-trifluoroethoxy)benzimidazole-7-carboxylate(0.48 g) according to the procedure for Working Example 28.

m.p.: 210-212° C.

Elemental Analysis for C₂₅H₁₉F₃N₆O₃:

C (%) H (%) N (%) Calcd.: 59.06; 3.77; 16.53 Found: 59.02; 3.71; 16.36

¹H-NMR(200 MHz,CDCl₃) δ: 3.82(3H,s), 5.01(2H,q), 5.64(2H,s), 6.99(2H,d),7.14(2H,d), 7.25(1H,t), 7.37-7.41(1H,m), 7.51-7.63(3H,m), 7.71(1H,dd),8.17-8.22(1H,m)

IR(KBr) cm⁻¹: 1710, 1550, 1425, 1275, 1240, 1180, 1160, 1055, 750

Working Example 771-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-2-(2,2,2-trifluoroethoxy)benzimidazole-7-carboxylicacid

The title compound was prepared as colorless crystals (0.23 g, 88%) frommethyl1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]-2-(2,2,2-trifluoroethoxy)benzimidazole-7-carboxylate(0.27 g) according to the procedure for Working Example 47.

m.p.: 204-206° C.

Elemental Analysis for C₂₄H₁₇F₃N₆O₃.H₂O:

C (%) H (%) N (%) Calcd.: 57.26; 3.60; 16.69 Found: 57.09; 3.59; 16.72

¹H-NMR(200 MHz,DMSO-d₆) δ: 5.28(2H,q), 5.66(2H,s), 6.98(4H,d),7.23(1H,t), 7.44-7.68(5H,m), 7.72(1H,dd)

IR(KBr) cm⁻¹: 1690, 1540, 1470, 1430, 1270, 1225, 1210, 1160, 1050, 740

The following compounds as listed in Table 1 are prepared according tothe procedures for Reference Examples and Working Examples disclosedherein.

TABLE 1

Compound No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) R^(6a) 78 OEt Me H H TetCOOH 79 OEt OMe H H Tet COOH 80 OEt NHMe H H Tet COOH 81 OEt F H H TetCOOH 82 OEt Cl H H Tet COOH 83 OEt Br H H Tet COOH 84 OEt CF₃ H H TetCOOH 85 OEt H Me H Tet COOH 86 OEt H OMe H Tet COOH 87 OEt H NHMe H TetCOOH 88 OEt H F H Tet COOH 89 OEt H Cl H Tet COOH 90 OEt H Br H Tet COOH91 OEt H CF₃ H Tet COOH 92 OEt H H Me Tet COOH 93 OEt H H OMe Tet COOH94 OEt H H NHMe Tet COOH 95 OEt H H F Tet COOH 96 OEt H H Cl Tet COOH 97OEt H H Br Tet COOH 98 OEt H H CF₃ Tet COOH 99 OEt Me H H COOH COOH 100OEt H Me H COOH COOH 101 OEt H H Me COOH COOH 102 OEt H H H COOH COOH103 OEt Cl H H COOH COOH 104 OEt H Cl H COOH COOH 105 OEt H Cl H COOHCOOH 106 SEt Me H H Tet COOH 107 NHMe H Me H Tet COOH 108 OMe H H Me TetCOOH 109 OPr H H Me Tet COOH 110 SMe Me H H Tet COOH 111 OMe H H H TetTet 112 OEt H H H Tet Tet 113 OEt Me H H Tet Tet 114 OEt H

Tet COOH 115 OEt

H Tet COOH 116 OEt H H H Tet COOCH₂COO-cyclo-Pr 117 OEt H H H TetCOOCH₂COO-sec-Bu 118 OEt H H H Tet COOCH₂COO-n-Bu 119 OEt H H H TetCOOCH₂COO-cyclo-Bu 120 OEt H H H Tet COOCH₂COO-n-Pen 121 OEt H H H TetCOOCH₂COO-i-Pen 122 OEt H H H Tet COOCH₂COO-sec-Pen 123 OEt H H H TetCOOCH₂COO-n-Hex 124 OEt H H H Tet COOCH₂COO-sec-Hex 125 OEt H H H TetCOOCH₂COO-n-Hep 126 OEt H H H Tet COOCH₂OCOCH₂Ph 127 OEt H H H TetCOOCH(Me)—OCOEt 128 OEt H H H Tet COOCH(Me)—OCO-n-Pr 129 OEt H H H TetCOOCH(Me)—OCO-i-Pr 130 OEt H H H Tet COOCH(Me)—OCO-cyclo-Pr 131 OEt H HH Tet COOCH(Me)—OCO-n-Bu 132 OEt H H H Tet COOCH(Me)—OCO-i-Bu 133 OEt HH H Tet COOCH(Me)—OCO-sec-Bu 134 OEt H H H Tet COOCH(Me)—OCO-tert-Bu 135OEt H H H Tet COOCH(Me)—OCO-cyclo-Bu 136 OEt H H H TetCOOCH(Me)—OCO-n-Pen 137 OEt H H H Tet COOCH(Me)—OCO-i-Pen 138 OEt H H HTet COOCH(Me)—OCO-sec-Pen 139 OEt H H H Tet COOCH(Me)—OCO-cyclo-Pen 140OEt H H H Tet COOCH(Me)—OCO-n-Hex 141 OEt H H H Tet COOCH(Me)—OCO-i-Hex142 OEt H H H Tet COOCH(Me)—OCO-sec-Hex 143 OEt H H H TetCOOCH(Me)—OCO-cyclo-Hex 144 OEt H H H Tet COOCH(Me)—OCO-n-Hep 145 OEt HH H Tet COOCH(Et)—OCO-n-Pr 146 OEt H H H Tet COOCH(Pr)—OCO-n-Bu 147 OEtH H H Tet COOCH(iPr)—OCO-n-Pr 148 OEt H H H Tet COOCH(Me)—OCO—OMe 149OEt H H H Tet COOCH(Me)—OCO—O-n-Pr 150 OEt H H H TetCOOCH(Me)—OCO—O-i-Bu 151 OEt H H H Tet COOCH(Me)—OCO—O-sec-Bu 152 OEt HH H Tet COOCH(Me)—OCO—O-n-Pen 153 OEt H H H Tet COOCH(Me)—OCO—O-i-Pen154 OEt H H H Tet COOCH(Me)—OCO—O-cyclo-Pen 155 OEt H H H TetCOOCH(Me)—OCO—O-n-Hex 156 OEt H H H Tet COOCH(Me)—OCO—O-cyclo-Hex 157OEt H H H Tet COOCH(Me)—OCO—O-cyclo-Hex 158 OMe H H H TetCOOCH₂OCO-tert-Bu 159 OPr H H H Tet COOCH₂OCO-tert-Bu 160 OMe H H H TetCOOCH(Me)—OCO—O-cyclo-Hex 161 OPr H H H Tet COOCH(Me)—OCO—O-cyclo-Hex162 NHEt H H H Tet COOCH₂OCO-tert-Bu 163 NHEt H H H TetCOOCH₂OCO—O-cyclo-Hex

Experimental Example 1 Stable C-type crystalline1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylateand preparation thereof

1-(Cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylateis usually purified by column chromatography on silica gel and theeluted fraction is concentrated to dryness to give amorphous powders.The powder is unstable by heat and impractical in production. Forsolving this problem, the present inventors made extensive experimentson crystallization of the subject compound and discovered C-typecrystalline form. The C-type crystal is unexpectedly stable by heat andquite useful for production. The C-type crystal of the title compoundhas approximately the following lattice spacings:

3.5 angstrom; middle

3.7 angstrom; weak

3.8 angstrom; middle

4.0 angstrom; middle

4.1 angstrom; weak

4.3 angstrom; weak

4.4 angstrom; middle

4.6 angstrom; middle

4.8 angstrom; middle

5.1 angstrom; middle

5.2 angstrom; weak

6.9 angstrom; weak

7.6 angstrom; weak

8.8 angstrom; middle

9.0 angstrom; strong

15.9 angstrom; weak

IR spectrum (KBr tablet) of the C-type crystal is shown in FIG. 2 withthe significant absorption maxima at 2942, 1754, 1717, 1615, 1549, 1476and 750 cm⁻¹ and its melting point is 158-166° C. (decomposition).Representative X ray chart (powder method), IR spectra (KBr tablet) anddifferential scanning calorimeter patterns are shown in FIGS. 1-3,respectively.

The C-type crystal of1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylatehas advantages, for example;

1. It improves heat stability and practical utility.

2. Residual solvent can be minimized in crystals.

3. It can achieve industrial and clinical developments and giveecomomical benefits.

The concentrated residues, amorphous powders, and/or crystals except forthe C-type crystal for obtaining the subject compound, are stirred in asuitable solvent to form the desired C-type crystal. In case where theC-type crystal is not formed, a small amount of the C-type crystal canbe added as a seed to allow crystallization. Examples of such solventsare not limited to, as long as they afford the C-type crystal, butinclude lower alcohols (e.g. methanol, ethanol, isopropyl alcohol,etc.), a mixture of lower alcohol and water and a mixture of lower alkylketone (e.g. acetone, etc.) and water. Amounts of solvents used are notlimited to, but practically, 2 to 30-fold per weight of the crystal.Ratios of lower alcohol vs. water and lower alkyl ketone vs. water arenot limited to, but preferably 4:1 to 1:1. Stirring temperatures are notlimited to, but −5° C. to 40°C., preferably 0° C. to 25° C.

Experimental Example 2 Inhibition of binding of angiotensin II toangiotensin receptor

[Method]

An experiment of inhibition on the binding of angiotensin II (AII) toAII receptor was conducted by modifying the method of Douglas et al.[Endocrinology, 102, 685-696 (1978)]. An A II receptor membrane fractionwas prepared from bovine adrenal cortex.

The compound of the present invention (10⁻⁶ M or 10⁻⁷ M) and¹²⁵I-angiotensin II (¹²⁵I-A II) (1.85 kBq/50 μl) were added to thereceptor membrane fraction, and the mixture was incubated at roomtemperature for one hour. The receptor-bound and free ¹²⁵I-A II wereseparated through a filter (Whataan GF/B filter), and the radioactivityof ¹²⁵I-A II bound to the receptor was measured.

[Results]

The results relating to the compounds of the present invention are shownin Table 2.

Experimental Example 3 Inhibitory effect of the compound of the presentinvention on pressor action of A II

[Method]

Jcl: SD rats (9 week old, male) were employed. On the previous day ofthe experiment, these animals were applied with cannulation into thefemoral artery and vein under anesthesia with pentobarbital Na. Theanimals were fasted but allowed to access freely to drinking water untilthe experiment was started. Just on the day of conducting theexperiment, the artery cannula was connected with a blood-pressuretransducer, and the average blood pressure was recorded by means ofpolygraph. Before administration of the drug, the pressor action due tointravenous administration of A II (100 ng/kg) as the control wasmeasured. The drugs were orally administered, then, at each point of themeasurement, A II was administered intravenously, and the pressor actionwas similarly measured. By comparing the pressor action before and afteradministration of the drug, the percent inhibition by the drug on AII-induced pressor action was evaluated.

[Results]

The results relating to the compounds of the present invention are shownin Table 2.

TABLE 2

Working Radioreceptor Pressor Response Example Assay to A II(p.o.) No.R¹ Y R² R′ 1 × 10⁻⁷M 1 × 10⁻⁶M 3 mg/kg 28 Et O Tet COOEt 46 82 +++ a) 29Et O Tet COOH 61 91 +++ 30 Pr O Tet COOEt 16 48 +++ 31 Pr O Tet COOH 4079 +++ 33 Me S Tet COOEt 2 26 + 34 Et S Tet COOEt 17 54 +++ 35 Pr S TetCOOEt 7 32 NT 36 Me S Tet COOH 51 82 +++ 37 Et S Tet COOH 41 80 +++ 38Pr S Tet COOH 6 50 +++ 39 Et O Tet COOMe 58 89 +++ 40 Et NH Tet COOEt 5483 +++ 41 Pr NH Tet COOEt 45 57 NT b) 43 Et O Tet

74 94 +++ 44 Et O Tet

32 77 +++ 45 Me O Tet COOMe 17 67 +++ 46 Me O Tet COOH 66 88 +++ 47 EtNH Tet COOH 84 96 +++ 48 Pr NH Tet COOH 67 92 ++ 49 Et O Tet

66 91 +++ 50 Et O Tet COOCH₂OCOCH₃ 63 92 +++ 51 Et O Tet COOCH₂OCOEt 4484 +++ 52 Et O Tet COOCH₂OCOPr 48 84 +++ 53 Et O Tet COOCH₂OCOiPr 55 85+++ 54 Et O Tet

42 81 +++ 55 Et O Tet

63 91 +++ 56 Et O Tet

31 76 +++ 57 Me NH Tet COOH 41 79 NT 58 Et O Tet

55 84 +++ 59 Et O Tet

37 69 +++ 60 Et O Tet

44 81 +++ 61 Et O Tet

54 89 +++ 62 Et NH Tet COOCH₂OCOtBu 48 87 +++ 63 Et NH Tet

19 61 +++ a) +++ ≧ 70% > ++ ≧ 50% ≧ + > 30% > − b) NT, not tested

It is understood that the preceding representative examples may bevaried within the scope of the present invention by one skilled in theart to achieve essentially the same results.

As many widely different embodiments of this invention may be madewithout departing from the spirit and scope thereof, it is to beunderstood that this invention is not limited to the specificembodiments thereof except as defined in the appended claims.

What is claimed is:
 1. A compound of the formula:

wherein the ring A is a benzene ring which may be substituted orunsubstituted in addition to the R′ group; with a substituent selectedfrom the group consisting of 1) halogen; 2) nitro; 3) cyano; 4) amino;5) N—C₁₋₄, alkylamino; 6) N—N—di—C₁₋₄alkylamino; 7) phenylamino; 8)naphthylamino; 9) benzylamino; 10) naphthylmethylamino; 11) morpholino;12) piperidino; 13) piperazino; 14) N-phenylpiperazino; 15) a grouphaving the formula —W—R¹³ wherein W is i) a chemical bond, ii) —O—, iii)—S— or iv) —C(═O)— and R¹³ is i) hydrogen or ii) C₁₋₄ alkyl optionallysubstituted with a) hydroxyl, b) amino, c) dimethylamino, d)diethylamino, e) piperidino, f) morpholino, g) halogen or h) C₁₋₄alkoxy; 16) a group having a formula: —(CH₂)_(p)—CO—D wherein p is 0 or1, and D is i) hydrogen, ii) hydroxyl, iii) amino, iv) N—C₁₋₄alkylamino: v) N—N—di-C₁₋₄alkylamino; vi) C₁₋₆ alkoxy optionallysubstituted with a) hydroxyl, b) amino, c) dimethylamino, d)diethylamino, e) piperidino, f) morpholino, g) halogen, h) C₁₋₆ alkoxy,i) C₁₋₆ alkylthio, j) dioxolenyl or k) 5-methyl-2-oxo-1,3-dioxolen4-ylon the alkyl moiety, or vii) a group having the formula: —OCH(R⁹) OCOR¹⁰wherein R⁹ is a) hydrogen, b) straight or branched C₁₋₆alkyl, c)cyclopentyl, d) cyclohexyl, or e) cycloheptyl, and R¹⁰ is a) straight orbranched C₁₋₆alkyl, b) straight or branched C₂₋₈alkenyl, c) cyclopentyl,d) cyclohexyl, e) cycloheptyl, f) C₁₋₃alkyl which is substituted withphenyl, p-chlorophenyl or C₅₋₇cycloalkyl, g) C₂₋₃alkenyl which issubstituted with phenyl or C₅₋₇ cycloalkyl, h) phenyl, i) p-tolyl, j)naphthyl, k) straight or branched C₁₋₆alkoxy, l) straight or branchedC₂₋₈alkenyloxy, m) cyclopentyloxy, n) cyclohexyloxy, o) cycloheptyloxy,p) C₁₋₃alkoxy which is substituted with phenyl or C₅₋₇cycloalkyl, g)C₂₋₃alkenyloxy which is substituted with phenvl or C₅₋₇cycloalkyl, r)phenoxy, s) p-nitrophenoxy or t) naphthoxy; 17) tetrazolyl optionallyprotected with i) C₁₋₄alkyl optionally substituted with C₁₋₄alkoxy orphenyl, ii) C₂-₅ alkanoyl or iii) benzoyl; 18) trifluoromethanesulfonicamido; 19) phosphono (PO(OH)₂); and 20) sulfo (SO₂H); whereby one or twoof these substituents may be substituted at various positions of thebenzene ring, and whereby when two substituents are present at the 4 and5 or 5 and 6 positions on the ring A, they may be taken together to forma benzene ring whereby such rings may be substituted with the samegroups as for the ring A, R¹ is 1) hydrogen: 2) C₁₋₈alkalyl,C₂₋₈alkenyl, C₂₋₈alknyl or C₃₋₆cycloalkyl group which groups may besubstituted with i) hydroxyl, ii) amino, iii) methylamino iv) halogen orv) C₁₋₄alkoxy; 3) phenyl optionally substituted with i) halogen, ii)nitro, iii) C₁₋₄alkoxy or C₁₋₄alkyl; or 4) phenyl-C₁₋₄alkyl optionallysubstituted with i) haloen, ii) nitro, iii) C₁₋₄alkoxy or iv) C₁₋₄alkylon the benzene ring; and R² is 1) carboxyl; 2) tetrazolyl; 3)trifluoromethanesulfonic amido; 4) phosphono (PO(OH)₂); 5) sulfo (SO₃H);6) cyano; or 7) C₁₋₄alkoxycarbonyl; each of which may be protected withi) C₁₋₄alkyl optionally substituted with C₁₋₄alkoxy or phenyl, ii)C₂₋₅alkanoyl or iii) benzoyl; X is a chemical bond, C₁₋₄alkylene whereinthe number of carbon atoms in the straight chain of said C₁₋₄alkylene is1 or 2, —CO—, —O—, —S—, —NH—, —CONH—, —OCHI—, SCH₂— or —CH═CH—; R′ is agroup of the formula: —CO—D′ wherein D′ is hydroxy or lower (C₁₋₆)alkoxy optionally substituted with hydroxy, optionally substitutedamino, halogen, lower (C₁₋₆) alkoxy, lower (C₁₋₆) alkylthio oroptionally substituted dioxolenyl on the alkyl moiety; Y is —O—,—S(O)_(m)— or —N(R⁴)— wherein m is an integer of 0, 1 or 2 and R⁴ ishydrogen or optionally substituted alkyl group, wherein R¹ and R⁴ may betaken together with the N atom to form a ring and n is an integer of 1or 2; or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1, wherein R¹ is a C₁₋₅ alkyl or C₂₋₅ alkenyl groupoptionally substituted with halogen, hydroxyl, an amino group or a C₁₋₄alkoxy group.
 3. A compound or a salt thereof according to claim 1,wherein R¹ is phenyl which may be substituted with halogen, nitro, C₁₋₄alkoxy, or C₁₋₄ alkyl.
 4. A compound according to claim 1, wherein R¹ isphenyl-C₁₋₄ alkyl which may be substituted with halogen, nitro, C₁₋₄alkoxy, or C₁₋₄ alkyl.
 5. A compound or a salt thereof according toclaim 1, wherein R²is a tetrazolyl group optionally protected with C₁₋₄alkyl optionally substituted with C₁₋₄ alkoxy or phenyl, C₂₋₅ alkanoylor benzoyl, a carboxyl group optionally protected with C₁₋₄ alkyoptionaly substituted with C₁₋₄ alkoxy or phenyl, ortrifluoromethanesulfonic amide.
 6. A compound or a salt thereofaccording to claim 1, wherein R² is a tetrazolyl group.
 7. A compoundaccording to claim 1, wherein the ring A is a benzene ring whichcontains no substitution in addition to the R′ group.
 8. A compoundaccording to claim 1, wherein X is a chemical bond between the phenylenegroup and the phenyl group.
 9. A compound according to claim 1, which isethyl2-propoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylateor a pharmaceutically acceptable salt thereof.
 10. A compound accordingto claim 1, which is2-propoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid or a pharmaceutically acceptable salt thereof.
 11. A compoundaccording to claim 1, which is carboxylate or a pharmaceuticallyacceptable salt thereof.
 12. A compound according to claim 1, which isbenzimidazole-7-carboxylate or a pharmaceutically acceptable saltthereof.
 13. A compound according to claim 1, which isbenzimidazole-7-carboxylate or a pharmaceutically acceptable saltthereof.
 14. A compound according to claim 1, which is2-methylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid or a pharmaceutically acceptable salt thereof.
 15. A compoundaccording to claim 1, which is2-ethylthio-1-[[2′-(1H-tetrozol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid or a pharmaceutically acceptable salt thereof.
 16. A compoundaccording to claim 1, which is2-propylthio-l-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]bennzimidazole-7-carboxylicacid or a pharmaceutically acceptable salt thereof.
 17. A compoundaccording to claim 1, which is ethyl2-ethylamino-1-benzimidazole-7-carboxylate or a pharmaceuticallyacceptable salt thereof.
 18. A compound according to claim 1, which isethyl 2-propylamino-1-benzimidazole-7-carboxylate or a pharmaceuticallyacceptable salt thereof.
 19. A compound according to claim 1, which ismethyl 2-methoxy-1-benzimidazole-7 carboxylate acid or apharmaceutically acceptable salt thereof.
 20. A compound according toclaim 1, which is2-methoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid or a pharmaceutically acceptable salt thereof.
 21. A compoundaccording to claim 1, which is2-ethylamino-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylicacid or a pharmaceutically acceptable salt thereof.
 22. A compoundaccording to claim 1, which is2-propylamino-1-benzamidzaole-7-carboxylic acid or a pharmaetuecitcalluacceptable salt thereof.
 23. A compound according to claim 1, which is(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl2-ethoxy-1-benzyimdaloze-7-carboxlate or a pharmaceutically acceptablesalt thereof.
 24. A pharmaceutical composition for antagonizingangiotensin II which comprises a therapeutically effective amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof in admixture with a pharmaceutically acceptable carrier,excipient or diluent.
 25. A method for antagonizing angiotensin II in amammal which comprises administering to a mammal in need thereof atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.